Benzimidazole derivatives

ABSTRACT

The present invention relates to a compound of the Formula I 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , X, m, and n are as defined herein. Such novel benzamidazole derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

This application is a continuation of U.S. patent application Ser. No.12/142,119, filed Jun. 19, 2008, now allowed, which claims the benefitof U.S. Provisional Patent Application Ser. Nos. 60/947,287, filed Jun.29, 2007, and 61/041,645, filed Apr. 2, 2008, each of which are herebyincorporated by reference in their entirety.

FIELD OF INVENTION

This invention relates to novel benzimidazole derivatives that areuseful in the treatment of abnormal cell growth, such as cancer, inmammals. This invention also relates to a method of using such compoundsin the treatment of abnormal cell growth in mammals, especially humans,and to pharmaceutical compositions containing such compounds.

BACKGROUND

Hedgehog (Hh) proteins are secreted morphogens that are involved in manybiological processes during embryonic development. Postnatally, Hh hasimportant roles in tissue homeostasis and aberrant Hh signaling isassociated with developmental disorders and several types of cancer. Atthe cell surface, the Hh signal is thought to be relayed by the 12transmembrane domain protein Patched (Ptc) (Hooper and Scott, Cell 59:75 1-65 (1989); Nakano et al., Nature 341: 508-13 (1989)) and theG-protein-coupled-like receptor Smoothened (Smo) (Alcedo et al., Cell86: 221-232 (1996); van den Heuvel and Tngham, Nature 382: 547-551(1996)). Both genetic and biochemical evidence support a receptor modelwhere Ptch and Smo are part of a multi-component receptor complex (Chenand Struhl, Cell 87: 553-63 (1996); Mango et al., Nature 384: 176-9(1996); Stone et al., Nature 384:129-34 (1996)). Upon binding of Hh toPtch, the normal inhibitory effect of Ptch on Smo is relieved, allowingSmo to transduce the Hh signal across the plasma membrane. However, theexact mechanism by which Ptch controls Smo activity still has yet to beclarified.

The signaling cascade initiated by Smo results in activation of Glitranscription factors that translocate into the nucleus where theycontrol transcription of target genes. Gli has been shown to influencetranscription of Hh pathway inhibitors such as Ptc and Hip I in anegative feedback loop indicating that tight control of the Hh pathwayactivity is required for proper cellular differentiation and organformation. Uncontrolled activation of Hh signaling pathway is associatedwith malignancies in particular those of the brain, skin and muscle aswell as angiogenesis. An explanation for this is that the Hh pathway hasbeen shown to regulate cell proliferation in adults by activation ofgenes involved in cell cycle progression such as cyclin D which isinvolved in G1-S transition. Also, Sonic Hedgehog (SHh), an ortholog ofHh, blocks cell-cycle arrest mediated by p21, an inhibitor of cyclindependent kinases. Hh signaling is further implicated in cancer byinducing components in the EGFR pathway (EGF, Her2) involved inproliferation as well as components in the PDGF (PDGFa) and VEGFpathways involved in angiogenesis. Loss of function mutations in thePtch gene have been identified in patients with the basal cell nevussyndrome (BCNS), a hereditary disease characterized by multiple basalcell carcinomas (BCCs). Dysfunctional Ptch gene mutations have also beenassociated with a large percentage of sporadic basal cell carcinomatumors (Chidambaram et al., Cancer Research 56: 4599-601 (1996); Gailaniet al., Nature Genet. 14: 78-81 (1996); Hahn et al., Cell 85: 841-51(1996); Johnson et al., Science 272: 1668-71 (1996); Unden et al.,Cancer Res. 56: 4562-5; Wicking et al., Am. J. Hum. Genet. 60: 21-6(1997)). Loss of Ptch function is thought to cause an uncontrolled Smosignaling in basal cell carcinoma. Similarly, activating Smo mutationshave been identified in sporadic BCC tumors (Xie et al., Nature 391:90-2 (1998)), emphasizing the role of Smo as the signaling subunit inthe receptor complex for SHh. Various inhibitors of hedgehog signalinghave been investigated such as Cyclopamine, a natural alkaloid that hasbeen shown to arrest cell cycle at G0-GI and to induce apoptosis inSCLC. Cyclopamine is believed to inhibit Smo by binding to itsheptahelical bundle. Forskolin has been shown to inhibit the Hh pathwaydownstream from Smo by activating protein kinase A (PKA) which maintainsGli transcription factors inactive. Despite advances with these andother compounds, there remains a need for potent inhibitors of thehedgehog signaling pathway.

SUMMARY OF THE INVENTION

The present invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt wherein:

each R¹ is independently selected from the group consisting of halo,—(CH₂)_(t)OH, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —NO₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)(C═O)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)N[(CH₂)_(t)R⁹]S(O)_(w)[(CH₂)_(t)R⁹],—(CH₂)_(t)S(O)_(w)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)S(O)_(w)[(CH₂)_(t)R⁹],—(CH₂)_(t)R⁹, —(CH₂)_(t)O[(CH₂)_(t)R⁹], —(CH₂)_(t)(C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)(C═O)O[(CH₂)_(t)R⁹], —(CH₂)_(t)O(C═O)[(CH₂)_(t)R⁹],—N[(CH₂)_(t)R⁹](C═O)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀ aryl), and —(CH₂)_(t)(4 to 14 membered heterocyclyl)wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃, and—N[(CH₂)_(t)R⁹]₂;

R² is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(q)OH, —(C═O)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(q)O(C₁-C₆)alkyl,—(CH₂)_(q)O(C₁-C₆)alkylOH, —(CH₂)_(p)CF₃, and —(CH₂)_(p)CN;

each R^(3A) is independently selected from the group consisting ofhydrogen, —CN, halo, hydroxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(4 to 14 membered heterocyclyl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(C═O)(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 4 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein each said alkyl, cycloalkyl,aryl, and heterocyclyl may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl;

each R^(3B) is selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(4 to 14 membered heterocyclyl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(C═O)(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein saidheterocyclyl ring has 1 to 4 ring heteroatoms selected from N, O, or S,and wherein said alkyl, cycloalkyl, aryl, and heterocyclyl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl;

any R^(3A) and R^(3B) or any two R^(3A) or any two R^(3B) can be takentogether to form an additional carbocyclic ring of from 3 to 9 membersthereby forming bridged, fused or spiro cyclic systems, said carbocyclicring may optionally contain up to 2 double bonds;

R² and R^(3B) on the nitrogen can be taken together to form anadditional heterocyclic ring of from 6 to 9 members thereby formingbridged, fused or spiro cyclic systems, said carbocyclic ring mayoptionally contain up to 2 double bonds;

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(q)OH, —(CH₂)_(q)O(C₁-C₆)alkyl, —(CH₂)_(q)O(C₁-C₆)alkylOH,—(CH₂)_(p)CF₃, —(CH₂)_(p)CN, —(CH₂)_(p)NH₂, —(CH₂)_(p)NH(C₁-C₆)alkyl,and —(CH₂)_(p)N[(C₁-C₆)alkyl]₂;

R⁵ is selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(p)(C₁-C₆)alkoxy,—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 membered heterocyclyl) and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, and whereineach said (CH₂) moiety, alkyl, alkynyl, alkenyl, carbocyclyl, aryl, andheterocyclyl are independently optionally substituted by 1 to 5substituents selected from R⁶;

each R⁶ is independently selected from the group consisting of azide,halo, —NO₂, —OR⁷, —(CH₂)_(t)(R⁷), —CF₃, —OCF₃, —OCHF₂, —OCH₂F,—O(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl(R⁷), —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(CH₂)_(t)SR⁷,—(CH₂)_(t)(S═O)R⁷, —(CH₂)_(t)S(═O)₂R⁷, —[C(R⁶)₂]_(t)N(R⁷)S(═O)₂R⁷,—S(═O)₂N(R⁷)₂, —(C═O)R⁷, —(C═O)OR⁷, —[C(R⁷)₂]_(t)O(C═O)R⁷,—[C(R⁷)₂]_(t)O(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷, —[C(R⁷)₂]_(t)N(R⁷)(C═O)OR⁷,—[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂N(R)₂,—[C(R⁷)₂]_(t)N(R⁷)N(R⁷)₂, —(C═O)N(R⁷)₂, —O(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷,—C(R⁷)₂SR⁷, —[C(R⁷)₂]_(t)(S═O)R⁷, —[C(R⁷)₂]_(t)S(═O)₂R⁷,—[C(R⁷)₂]_(t)S(═O)₂N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)(C═O)OR⁷, —C(R⁷)═NN(R⁷)₂, —C(R⁷)═NOR⁷,—C(R⁷)₂N(R⁷)N(R)₂, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂N(R⁷)₂, and—[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂;

each R⁷ is independently selected from H, —CF₃, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₂)carbocyclyl, and—(C₆-C₁₀)aryl, or two R⁷ groups on the same nitrogen atom may be takentogether with the nitrogen atom to form a 5 to 8 membered heterocyclylring, wherein said heterocyclyl ring has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, or two R⁷ groups onthe same carbon atom may be taken together with the carbon atom to forma 3 to 7 membered carbocyclyl ring and wherein each said alkyl, alkenyl,aryl, heterocyclyl and carbocyclyl may optionally be substituted by oneto three substituents independently selected from the group consistingof halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl;

X is selected from the group consisting of O, S, and NR⁸;

R⁸ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(t)C≡N, —NO₂, and —S(═O)₂R⁹;

each R⁹ is independently selected from the group consisting of H,—(C₁-C₆)alkyl, —(CH₂)_(t)OH, —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, or two R⁹ groups onthe same nitrogen atom may be taken together with the nitrogen atom toform a 5 to 8 membered heterocyclyl ring wherein said heterocyclyl ringoptionally has 1 to 3 ring additional heteroatoms selected from thegroup consisting of N, O, and S, or two R⁹ groups on the same carbonatom may be taken together with the carbon atom to form a 3 to 7membered carbocyclyl ring, wherein each said alkyl, aryl, (CH₂) moiety,carbocyclyl, and heterocyclyl may optionally be substituted by one tothree substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃,—(CH₂)_(t)(C₆-C₁₀ aryl), —NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]₂ and—(CH₂)_(t)(4 to 14 membered heterocyclyl) wherein said heterocyclyl has1 to 3 ring heteroatoms selected from the group consisting of N, O, andS;

each p is an integer independently selected from 1, 2, 3, 4, or 5;

each t is an integer independently selected from 0, 1, 2, 3, 4, or 5;

each m is an integer independently selected from 0, 1 or 2;

each n is an integer independently selected from 0, 1, 2, 3, or 4;

each q is an integer independently selected from 2, 3, 4, or 5; and

each w is an integer independently selected from 0, 1, or 2.

In another embodiment is provided a compound of Formula I:

or a pharmaceutically acceptable salt wherein:

each R¹ is independently selected from the group consisting of halo,—(CH₂)_(t)OH, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —NO₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)(C═O)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)N[(CH₂)_(t)R⁹]S(O)_(w)[(CH₂)_(t)R⁹],—(CH₂)_(t)S(O)_(w)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)S(O)_(w)[(CH₂)_(t)R⁹],—(CH₂)_(t)R⁹, —(CH₂)_(t)O[(CH₂)_(t)R⁹], —(CH₂)_(t)(C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)(C═O)O[(CH₂)_(t)R⁹], —(CH₂)_(t)O(C═O)[(CH₂)_(t)R⁹],—N[(CH₂)_(t)R⁹](C═O)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, and —(CH₂)_(t)(4 to 14 membered heterocyclyl)wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃, and—N[(CH₂)_(t)R⁹]₂;

R² is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(q)OH, —(C═O)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(q)O(C₁-C₆)alkyl,—(CH₂)_(q)O(C₁-C₆)alkylOH, —(CH₂)_(p)CF₃, and —(CH₂)_(p)CN;

each R^(3A) is independently selected from the group consisting ofhydrogen, —CN, halo, hydroxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 membered heterocyclyl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀ aryl), and—(CH₂)_(t)(C═O)(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein eachsaid heterocyclyl has 1 to 4 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein each said alkyl, carbocyclyl,aryl, and heterocyclyl may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl;

each R^(3B) is independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 membered heterocyclyl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)O(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀)aryl, and—(CH₂)_(t)(C═O)(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein eachsaid heterocyclyl ring has 1 to 4 ring heteroatoms selected from N, O,and S, and wherein each said alkyl, carbocyclyl, aryl, and heterocyclylmay optionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl; or

any R^(3A) and R^(3B) or any two R^(3A) or any two R^(3B) can be takentogether to form an additional carbocyclic ring of from 3 to 9 membersthereby forming bridged, fused or spiro cyclic system, said carbocyclicring may optionally contain up to 2 double bonds; or

R² and R^(3B) on the nitrogen can be taken together to form anadditional heterocyclic ring of from 6 to 9 members thereby formingbridged, fused or spiro cyclic system, said heterocyclic ring mayoptionally contain up to 2 double bonds;

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(q)OH, —(CH₂)_(q)O(C₁-C₆)alkyl, —(CH₂)_(q)O(C₁-C₆)alkylOH,—(CH₂)_(p)CF₃, —(CH₂)_(p)CN, —(CH₂)_(p)NH₂, —(CH₂)_(p)NH(C₁-C₆)alkyl,and —(CH₂)_(p)N[(C₁-C₆)alkyl]₂;

R⁵ is selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(p)(C₁-C₆)alkoxy,—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 membered heterocyclyl) and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein eachsaid heterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, and whereineach said (CH₂) moiety, alkyl, alkynyl, alkenyl, carbocyclyl, aryl, andheterocyclyl are independently optionally substituted by 1 to 5substituents selected from R⁶;

each R⁶ is independently selected from the group consisting of azide,halo, —NO₂, —OR⁷, —(CH₂)_(t)(R⁷), —CF₃, —OCF₃, —OCHF₂, —OCH₂F,—O(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl(R⁷), —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(CH₂)_(t)SR⁷,—(CH₂)_(t)(S═O)R⁷, —(CH₂)_(t)S(═O)₂R⁷, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂R⁷,—S(═O)₂N(R⁷)₂, —(C═O)R⁷, —(C═O)OR⁷, —[C(R⁷)₂]_(t)O(C═O)R⁷,—[C(R⁷)₂]_(t)O(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷, —[C(R⁷)₂]N(R⁷)(C═O)OR⁷,—[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂N(R)₂,—[C(R⁷)₂]_(t)N(R⁷)N(R⁷)₂, —(C═O)N(R⁷)₂, —O(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷,—C(R⁷)₂SR⁷, —[C(R)₂]_(t)(S═O)R⁷, —[C(R)₂]_(t)S(═O)₂R⁷,—[C(R⁷)₂]_(t)S(═O)₂N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷,—[C(R⁷)₂]N(R⁷)(C═O)OR⁷, —C(R⁷)═NN(R⁷)₂, —C(R⁷)═NOR⁷, —C(R⁷)₂N(R⁷)N(R)₂,—[C(R⁷)₂]_(t)N(R⁷)S(═O)₂N(R⁷)₂, and —[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R)₂;

each R⁷ is independently selected from H, —CF₃, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₂)carbocyclyl, and—(C₆-C₁₀)aryl, or two R⁷ groups on the same nitrogen atom may be takentogether with the nitrogen atom to form a 5 to 8 membered heterocyclylring, wherein said heterocyclyl ring has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, or two R⁷ groups onthe same carbon atom may be taken together with the carbon atom to forma 3 to 7 membered carbocyclyl ring and wherein each said alkyl, alkenyl,aryl, heterocyclyl and carbocyclyl may optionally be substituted by oneto three substituents independently selected from the group consistingof halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl;

X is selected from the group consisting of O, S, and NR⁸;

R⁸ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(t)C≡N, —NO₂, and —S(═O)₂R⁹;

each R⁹ is independently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(CH₂)_(t)OH, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, or two R⁹ groups onthe same nitrogen atom may be taken together with the nitrogen atom toform a 5 to 8 membered heterocyclyl ring wherein said heterocyclyl ringoptionally has 1 to 3 ring additional heteroatoms selected from thegroup consisting of N, O, and S, or two R⁹ groups on the same carbonatom may be taken together with the carbon atom to form a 3 to 7membered carbocyclyl ring, wherein each said alkyl, aryl, (CH₂) moiety,carbocyclyl, and heterocyclyl may optionally be substituted by one tothree substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃,—(CH₂)_(t)(C₆-C₁₀)aryl, —NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]₂ and—(CH₂)_(t)(4 to 14 membered heterocyclyl) wherein said heterocyclyl has1 to 3 ring heteroatoms selected from the group consisting of N, O, andS;

each p is independently 1, 2, 3, 4, or 5;

each t is independently 0, 1, 2, 3, 4, or 5;

each m is independently 0, 1 or 2;

each n is independently 0, 1, 2, 3, or 4;

each q is independently 2, 3, 4, or 5; and

each w is independently 0, 1, or 2;

provided that the compound of Formula I is not2-amino-N-[(3R,5S)-5-[5-(phenylmethyl)-1H-benzimidazol-2-yl]-3-pyrrolidinyl]-acetamide.

In still another embodiment is provided a compound of Formula I:

or a pharmaceutically acceptable salt wherein:

each R¹ is independently selected from the group consisting of halo,—(CH₂)_(t)OH, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —NO₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)(C═O)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)N[(CH₂)_(t)R⁹]S(O)_(w)[(CH₂)_(t)R⁹],—(CH₂)_(t)S(O)_(w)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)S(O)_(w)[(CH₂)_(t)R⁹],—(CH₂)_(t)R⁹, —(CH₂)_(t)O[(CH₂)_(t)R⁹], —(CH₂)_(t)(C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)(C═O)O[(CH₂)_(t)R⁹], —(CH₂)_(t)O(C═O)[(CH₂)_(t)R⁹],—N[(CH₂)_(t)R⁹](C═O)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, and —(CH₂)_(t)(4 to 14 membered heterocyclyl)wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃, and—N[(CH₂)_(t)R⁹]₂;

R² is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(q)OH, —(C═O)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(q)O(C₁-C₆)alkyl,—(CH₂)_(q)O(C₁-C₆)alkylOH, —(CH₂)_(p)CF₃, and —(CH₂)_(p)CN;

each R^(3A) is independently selected from the group consisting ofhydrogen, —CN, halo, hydroxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 membered heterocyclyl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀ aryl), and—(CH₂)_(t)(C═O)(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein eachsaid heterocyclyl has 1 to 4 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein each said alkyl, carbocyclyl,aryl, and heterocyclyl may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl;

each R^(3B) is independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —CF₃,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 membered heterocyclyl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)O(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀)aryl, and—(CH₂)_(t)(C═O)(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein eachsaid heterocyclyl ring has 1 to 4 ring heteroatoms selected from N, O,and S, and wherein each said alkyl, carbocyclyl, aryl, and heterocyclylmay optionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl; or

any R^(3A) and R^(3B) or any two R^(3A) or any two R^(3B) can be takentogether to form an additional carbocyclic ring of from 3 to 9 membersthereby forming bridged, fused or spiro cyclic system, said carbocyclicring may optionally contain up to 2 double bonds; or

R² and R^(3B) on the nitrogen can be taken together to form anadditional heterocyclic ring of from 6 to 9 members thereby formingbridged, fused or spiro cyclic system, said heterocyclic ring mayoptionally contain up to 2 double bonds;

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(q)OH, —(CH₂)_(q)O(C₁-C₆)alkyl, —(CH₂)_(q)O(C₁-C₆)alkylOH,—(CH₂)_(p)CF₃, —(CH₂)_(p)CN, —(CH₂)_(p)NH₂, —(CH₂)_(p)NH(C₁-C₆)alkyl,and —(CH₂)_(p)N[(C₁-C₆)alkyl]₂;

R⁵ is selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(p)(C₁-C₆)alkoxy,—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 membered heterocyclyl) and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein eachsaid heterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, and whereineach said (CH₂) moiety, alkyl, alkynyl, alkenyl, carbocyclyl, aryl, andheterocyclyl are independently optionally substituted by 1 to 5substituents selected from R⁶;

each R⁶ is independently selected from the group consisting of azide,halo, —NO₂, —OR⁷, —(CH₂)_(t)(R⁷), —CF₃, —OCF₃, —OCHF₂, —OCH₂F,—O(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl(R⁷), —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(CH₂)_(t)SR⁷,—(CH₂)_(t)(S═O)R⁷, —(CH₂)_(t)S(═O)₂R⁷, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂R⁷,—S(═O)₂N(R⁷)₂, —(C═O)R⁷, —(C═O)OR⁷, —[C(R⁷)₂]_(t)O(C═O)R⁷,—[C(R⁷)₂]_(t)O(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷, —[C(R⁷)₂]_(t)N(R⁷)(C═O)OR⁷,—[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂N(R)₂,—[C(R⁷)₂]_(t)N(R⁷)N(R⁷)₂, —(C═O)N(R⁷)₂, —O(C═O)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷,—C(R⁷)₂SR⁷, —[C(R⁷)₂]_(t)(S═O)R⁷, —[C(R⁷)₂]_(t)S(═O)₂R⁷,—[C(R⁷)₂]_(t)S(═O)₂N(R⁷)₂, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)(C═O)OR⁷, —C(R⁷)═NN(R⁷)₂, —C(R⁷)═NOR⁷,—C(R⁷)₂N(R⁷)N(R)₂, —[C(R⁷)₂]_(t)N(R⁷)S(═O)₂N(R⁷)₂, and—[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂;

each R⁷ is independently selected from H, —CF₃, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₂)carbocyclyl, and—(C₆-C₁₀)aryl, or two R⁷ groups on the same nitrogen atom may be takentogether with the nitrogen atom to form a 5 to 8 membered heterocyclylring, wherein said heterocyclyl ring has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, or two R⁷ groups onthe same carbon atom may be taken together with the carbon atom to forma 3 to 7 membered carbocyclyl ring and wherein each said alkyl, alkenyl,aryl, heterocyclyl and carbocyclyl may optionally be substituted by oneto three substituents independently selected from the group consistingof halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl;

X is selected from the group consisting of O, S, and NR⁸;

R⁸ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(t)C≡N, —NO₂, and —S(═O)₂R⁹;

each R⁹ is independently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(CH₂)_(t)OH, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, or two R⁹ groups onthe same nitrogen atom may be taken together with the nitrogen atom toform a 5 to 8 membered heterocyclyl ring wherein said heterocyclyl ringoptionally has 1 to 3 ring additional heteroatoms selected from thegroup consisting of N, O, and S, or two R⁹ groups on the same carbonatom may be taken together with the carbon atom to form a 3 to 7membered carbocyclyl ring, wherein each said alkyl, aryl, (CH₂) moiety,carbocyclyl, and heterocyclyl may optionally be substituted by one tothree substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃,—(CH₂)_(t)(C₆-C₁₀)aryl, —NH(C₁-C₆)alkyl, —N[(C₁-C₆)alkyl]₂ and—(CH₂)_(t)(4 to 14 membered heterocyclyl) wherein said heterocyclyl has1 to 3 ring heteroatoms selected from the group consisting of N, O, andS;

each p is independently 1, 2, 3, 4, or 5;

each t is independently 0, 1, 2, 3, 4, or 5;

each m is independently 1 or 2;

each n is independently 0, 1, 2, 3, or 4;

each q is independently 2, 3, 4, or 5; and

each w is independently 0, 1, or 2.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein the 4 position hasabsolute configuration R.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein the 4 position hasabsolute configuration R and the 2 position has absolute configurationR.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R¹ isindependently selected from the group consisting of halo, —(CH₂)_(t)OH,—(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —NO₂, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)(C═O)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C═O)[(CH₂)_(t)R⁹], —(CH₂)_(t)R⁹,—(CH₂)_(t)O[(CH₂)_(t)R⁹], —(CH₂)_(t)(C═O)[(CH₂)_(t)R⁹],—(CH₂)_(t)(C═O)O[(CH₂)_(t)R⁹], —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀ aryl), and —(CH₂)_(t)(4 to 14 membered heterocyclyl)wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected from the group consisting of—(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃, and—N[(CH₂)_(t)R⁹]₂.

In another embodiment the invention relates to a compound of Formula Ior a pharmaceutically acceptable salt thereof wherein each R¹ isindependently selected from the group consisting of halo, —(CH₂)_(t)OH,—(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —NO₂, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)(C═O)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C═O)[(CH₂)_(t)R⁹], —(CH₂)_(t)R⁹,—(CH₂)_(t)O[(CH₂)_(t)R⁹], —(CH₂)_(t)(C═O)[(CH₂)_(t)R⁹], and—(CH₂)_(t)(C═O)O[(CH₂)_(t)R⁹], wherein each said (CH₂) moiety mayoptionally be substituted by one to two substituents independentlyselected from the group consisting of —(C₁-C₆)alkyl, halo, hydroxy,—(C₁-C₆)alkoxy, —CN, —(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂.

In another embodiment the invention relates to a compound of Formula Ior a pharmaceutically acceptable salt thereof wherein each R¹ isindependently selected from the group consisting of halo, —(CH₂)_(t)CF₃,—(CH₂)_(t)C≡N, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and—(CH₂)_(t)O[(CH₂)_(t)R⁹] wherein each said (CH₂) moiety may optionallybe substituted by one to two substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy,—CN, —(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂.

In another embodiment the invention relates to a compound of Formula Ior a pharmaceutically acceptable salt thereof wherein each R¹ is halo.

In another embodiment the invention relates to a compound of Formula Ior a pharmaceutically acceptable salt thereof wherein each R¹ is—(CH₂)_(t)CF₃, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selected from thegroup consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂.

In another embodiment the invention relates to a compound of Formula Ior a pharmaceutically acceptable salt thereof wherein each R¹ is—(CH₂)_(t)C≡N, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selected from thegroup consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R¹ is—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, wherein each said (CH₂) moiety may optionallybe substituted by one to two substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy,—CN, —(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R¹ is—(CH₂)_(t)R⁹, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selected from thegroup consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R¹ is—(CH₂)_(t)O[(CH₂)_(t)R⁹], wherein each said (CH₂) moiety may optionallybe substituted by one to two substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy,—CN, —(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂

In another embodiment the invention relates to a compound of Formula Ior a pharmaceutically acceptable salt thereof wherein R² is selectedfrom the group consisting of hydrogen, —(C₁-C₆)alkyl, —(CH₂)_(q)OH,—(C═O)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(q)O(C₁-C₆)alkyl,—(CH₂)_(q)O(C₁-C₆)alkylOH, —(CH₂)_(p)CF₃, and —(CH₂)_(p)CN.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is selected from thegroup consisting of hydrogen, —(C₁-C₆)alkyl, —(CH₂)_(q)OH,—(CH₂)_(p)CF₃, and —(CH₂)_(p)CN.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) isindependently selected from the group consisting of hydrogen, —CN, halo,hydroxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀aryl), —(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀ aryl), wherein each said alkyl,cycloalkyl, aryl, and heterocyclyl may optionally be substituted by oneto three substituents independently selected from the group consistingof halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) isindependently selected from the group consisting of hydrogen, —CN, halo,hydroxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(C═O)(CH₂)_(t)(C₆-C₁₀aryl), wherein each said alkyl, cycloalkyl, and aryl may optionally besubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) isindependently selected from the group consisting of hydrogen and—(C₁-C₆)alkyl, wherein each said alkyl may optionally be substituted byone to three substituents independently selected from the groupconsisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of hydrogen, —CN, halo,hydroxy, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀ aryl), and —(CH₂)_(t)(4to 14 membered heterocyclyl), wherein said heterocyclyl has 1 to 4 ringheteroatoms selected from the group consisting of N, O, and S, andwherein each said alkyl, cycloalkyl, aryl, and heterocyclyl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of hydrogen, —CN, halo,hydroxy, —(C₁-C₆)alkyl, —CF₃, —OCF₃, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(C₆-C₁₀aryl), wherein each said alkyl, cycloalkyl, and aryl may optionally besubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀ aryl), wherein each said alkyl, cycloalkyl, and aryl,may optionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) ishydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of —(C₁-C₆)alkyl,wherein said alkyl may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of —(C═O)O(C₁-C₆)alkyl,wherein said alkyl may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, wherein said carbocyclyl may optionallybe substituted by one to three substituents independently selected fromthe group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of —(CH₂)_(t)(C₆-C₁₀aryl), wherein said aryl may optionally be substituted by one to threesubstituents independently selected from the group consisting of halo,hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁴ is selected from thegroup consisting of hydrogen and —(C₁-C₆)alkyl.

In an embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁴ is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁴ is —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(p)(C₁-C₆)alkoxy,—(CH₂)_(t)O(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), —(CH₂)_(t)O(CH₂)_(t)(4 to 14 membered heterocyclyl) and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, and whereineach said (CH₂) moiety may optionally be substituted by one to twosubstituents independently selected substituents selected from R⁶, andwherein each said carbocyclyl, aryl, and heterocyclyl are independentlyoptionally substituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, wherein eachsaid (CH₂) moiety may optionally be substituted by one to twosubstituents independently selected substituents selected from R⁶, andwherein each said carbocyclyl, aryl, and heterocyclyl are independentlyoptionally substituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(C₆-C₁₀)aryl, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selected from R⁶,and wherein each said aryl and heterocyclyl are independently optionallysubstituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(C₆-C₁₀)aryl, and is selected from the group consisting of:

wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said aryl is independently optionally substituted by 1to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(C₆-C₁₀)aryl is selected from the group consisting of:

wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said aryl is independently optionally substituted by 1to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(C₆-C₁₀)aryl is selected from the group consisting of:

wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said aryl is independently optionally substituted by 1to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, wherein each said (CH₂) moiety mayoptionally be substituted by one to two substituents independentlyselected substituents selected from R⁶, and wherein each saidcarbocyclyl is independently optionally substituted by 1 to 3substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, wherein each said (CH₂) moiety mayoptionally be substituted by one to two substituents independentlyselected substituents selected from R⁶, and wherein each said aryl isindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl and is selected from the groupconsisting of:

wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said aryl is independently optionally substituted by 1to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is —(CH₂)_(t)(4 to14 membered heterocyclyl), wherein said heterocyclyl has 1 to 3 ringheteroatoms selected from the group consisting of N, O, and S, andwherein one or two carbon atoms of said heterocyclyl are optionallysubstituted with an oxo group, and wherein each said (CH₂) moiety mayoptionally be substituted by one to two substituents independentlyselected substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein each said (CH₂) moiety mayoptionally be substituted by one to two substituents independentlyselected substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl) is selectedfrom the group consisting of:

wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said heterocyclyl is independently optionallysubstituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁶ isindependently selected from the group consisting of azide, halo, —NO₂,—OR⁷, —(CH₂)_(t)(R⁷), —CF₃, —OCF₃, —OCHF₂, —OCH₂F,—O(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl(R⁷), —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(CH₂)_(t)SR⁷, —(C═O)R⁷,—(C═O)OR⁷, —[C(R⁷)₂]_(t)O(C═O)R⁷, —[C(R⁷)₂]_(t)O(C═O)N(R)₂,—[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —[C(R⁷)₂]_(t)OR⁷,—[C(R⁷)₂]_(t)N(R⁷)(C═O)OR⁷, —[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂,—[C(R⁷)₂]_(t)N(R⁷)N(R⁷)₂, —(C═O)N(R⁷)₂, —O(C═O)N(R)₂, —[C(R⁷)₂]_(t)OR⁷,—C(R⁷)₂SR⁷, —[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)(C═O)OR⁷,—C(R⁷)═NOR⁷ and —[C(R⁷)₂]_(t)N(R⁷)(C═O)N(R⁷)₂.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁶ isindependently selected from the group consisting of azide, halo, —NO₂,—OR⁷, —(CH₂)_(t)(R⁷), —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl(R⁷), —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(CH₂)_(t)SR⁷, —(C═O)R⁷,—(C═O)OR⁷, —[C(R⁷)₂]_(t)O(C═O)R⁷, —[C(R⁷)₂]_(t)O(C═O)N(R⁷)₂,—[C(R⁷)₂]_(t)N(R⁷)(C═O)R⁷, —[C(R⁷)₂]_(t)N(R)₂, and —[C(R⁷)₂]_(t)OR⁷.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁶ isindependently selected from the group consisting of azide, halo, —OR⁷,—CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and —[C(R⁷)₂]_(t)OR⁷.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁷ isindependently selected from the group consisting of H, —CF₃,—(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, or two R⁷ groups on the same nitrogen atommay be taken together with the nitrogen atom to form a 5 to 8 memberedheterocyclyl ring, wherein said heterocyclyl ring has 1 to 3 ringheteroatoms selected from the group consisting of N, O, and S, or two R⁷groups on the same carbon atom may be taken together with the carbonatom to form a 3 to 7 membered carbocyclyl ring and wherein said alkyl,cycloalkyl, aryl, heterocyclyl and carbocyclyl may optionally besubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁷ isindependently selected from the group consisting of H, —CF₃,—(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, wherein said alkyl, and aryl, mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—C(═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁷ is H.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁷ is —CF₃.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁷ is—(C₁-C₆)alkyl, wherein said alkyl may optionally be substituted by oneto three substituents independently selected from the group consistingof halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁷ is—(C₆-C₁₀)aryl, wherein said aryl may optionally be substituted by one tothree substituents independently selected from the group consisting ofhalo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is selected from thegroup consisting of O and S.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is S.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁸ is selected from thegroup consisting of hydrogen and —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁸ is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁸ is —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁹ isindependently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₀ aryl), —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,and —(CH₂)_(t)(4 to 14 membered heterocyclyl), wherein said heterocyclylhas 1 to 3 ring heteroatoms selected from the group consisting of N, O,and S, or two R⁹ groups on the same nitrogen atom may be taken togetherwith the nitrogen atom to form a 5 to 8 membered heterocyclyl ringwherein said heterocyclyl ring optionally has 1 to 3 ring additionalheteroatoms selected from the group consisting of N, O, and S, or two R⁹groups on the same carbon atom may be taken together with the carbonatom to form a 3 to 7 membered carbocyclyl ring, wherein each saidalkyl, aryl, (CH₂) moiety, carbocyclyl, and heterocyclyl may optionallybe substituted by one to three substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy,—CN, —(CH₂)_(t)CF₃, —(CH₂)_(t)(C₆-C₁₀ aryl), —NH(C₁-C₆)alkyl,—N[(C₁-C₆)alkyl]₂ and —(CH₂)_(t)(4 to 14 membered heterocyclyl) whereinsaid heterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁹ is—(C₁-C₆)alkyl, or wherein two R⁹ groups on the same carbon atom may betaken together with the carbon atom to form a 3 to 7 memberedcarbocyclyl ring, wherein each (CH₂) moiety may optionally besubstituted by one to two substituents independently selected from thegroup consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, —(CH₂)_(t)(C₆-C₁₀ aryl), —NH(C₁-C₆)alkyl,—N[(C₁-C₆)alkyl]₂ and —(CH₂)_(t)(4 to 14 membered heterocyclyl) whereinsaid heterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein each said alkyl may optionally besubstituted by one to three substituents independently selected from thegroup consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, —(CH₂)_(t)(C₆-C₁₀ aryl), —NH(C₁-C₆)alkyl,—N[(C₁-C₆)alkyl]₂ and —(CH₂)_(t)(4 to 14 membered heterocyclyl) whereinsaid heterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁹ is hydrogen.

In a embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein R² is selected from the group consisting of hydrogen and—(C₁-C₆)alkyl, wherein each (CH₂) moiety may optionally be substitutedby one to two substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein R² is hydrogen, wherein each (CH₂) moiety may optionally besubstituted by one to two substituents independently selected from thegroup consisting of —(C₁-C₆)alkyl, halo, hydroxy, —(C₁-C₆)alkoxy, —CN,—(CH₂)_(t)CF₃, and —N[(CH₂)_(t)R⁹]₂.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein each R^(3A) is independently selected from the groupconsisting of hydrogen and —(C₁-C₆)alkyl, wherein each said alkyl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein each R^(3A) is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) isindependently selected from the group consisting of hydrogen and—(C₁-C₆)alkyl, wherein each said alkyl may optionally be substituted byone to three substituents independently selected from the groupconsisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl, and wherein each R^(3B) is independently selectedfrom the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and—(CH₂)_(t)(C₆-C₁₀ aryl), wherein said alkyl, carbocyclyl, and aryl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) is hydrogenand wherein each R^(3B) is independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(C₆-C₁₀ aryl), wherein saidalkyl, carbocyclyl, or aryl may optionally be substituted by one tothree substituents independently selected from the group consisting ofhalo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein each R^(3B) is independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(C₆-C₁₀ aryl), wherein saidalkyl, alkenyl, carbocyclyl, and aryl may optionally be substituted byone to three substituents independently selected from the groupconsisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is selected from thegroup consisting of hydrogen and —(C₁-C₆)alkyl, and wherein each R^(3B)is independently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and—(CH₂)_(t)(C₆-C₁₀ aryl), wherein said alkyl, alkenyl, carbocyclyl, andaryl may optionally be substituted by one to three substituentsindependently selected from the group consisting of halo, hydroxy, —CN,—(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is hydrogen, andwherein each R^(3B) is independently selected from the group consistingof hydrogen, —(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and —(CH₂)_(t)(C₆-C₁₀ aryl), wherein saidalkyl, alkenyl, carbocyclyl, and aryl may optionally be substituted byone to three substituents independently selected from the groupconsisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein R⁴ is selected from the group consisting of hydrogen and—(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹],and wherein R⁴ is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and—(CH₂)_(t)(C₆-C₁₀ aryl), wherein said alkyl, alkenyl, carbocyclyl, andaryl may optionally be substituted by one to three substituentsindependently selected from the group consisting of halo, hydroxy, —CN,—(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl and wherein R⁴ is selected from the groupconsisting of hydrogen and —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and—(CH₂)_(t)(C₆-C₁₀ aryl), wherein said alkyl, alkenyl, carbocyclyl, andaryl may optionally be substituted by one to three substituentsindependently selected from the group consisting of halo, hydroxy, —CN,—(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl and wherein R⁴ is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R¹ is selected from thegroup consisting of halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N,—(CH₂)_(t)N[(CH₂)R⁹]₂, —(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹], andwherein R⁵ is selected from the group consisting of—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), and —(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, and wherein one ortwo carbon atoms of said heterocyclyl are optionally substituted with anoxo group, wherein each said (CH₂) moiety may optionally be substitutedby one to two substituents independently selected from R⁶, and whereineach said carbocyclyl, aryl, and heterocyclyl are independentlyoptionally substituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is selected from thegroup consisting of hydrogen and —(C₁-C₆)alkyl, and wherein R⁵ isselected from the group consisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, and whereineach said (CH₂) moiety may optionally be substituted by one to twosubstituents independently selected substituents selected from R⁶, andwherein each said carbocyclyl, aryl, and heterocyclyl are independentlyoptionally substituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R² is hydrogen andwherein R⁵ is selected from the group consisting of—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), and —(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, and wherein one ortwo carbon atoms of said heterocyclyl are optionally substituted with anoxo group, wherein each said (CH₂) moiety may optionally be substitutedby one to two substituents independently selected substituents selectedfrom R⁶, and wherein each said carbocyclyl, aryl, and heterocyclyl areindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) isindependently selected from the group consisting of hydrogen and—(C₁-C₆)alkyl, wherein each said alkyl may optionally be substituted byone to three substituents independently selected from the groupconsisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl, and wherein R⁵ is selected from the groupconsisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), and —(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, and wherein one ortwo carbon atoms of said heterocyclyl are optionally substituted with anoxo group, wherein each said (CH₂) moiety may optionally be substitutedby one to two substituents independently selected substituents selectedfrom R⁶, and wherein each said carbocyclyl, aryl, and heterocyclyl areindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3A) ishydrogen, and wherein R⁵ is selected from the group consisting of—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), and —(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, and wherein one ortwo carbon atoms of said heterocyclyl are optionally substituted with anoxo group, wherein each said (CH₂) moiety may optionally be substitutedby one to two substituents independently selected substituents selectedfrom R⁶, and wherein each said carbocyclyl, aryl, and heterocyclyl areindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R^(3B) isindependently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl, and—(CH₂)_(t)(C₆-C₁₀ aryl), wherein said alkyl, carbocyclyl, or aryl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl, andwherein R⁵ is selected from the group consisting of—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), and —(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, and wherein one ortwo carbon atoms of said heterocyclyl are optionally substituted with anoxo group, wherein each said (CH₂) moiety may optionally be substitutedby one to two substituents independently selected substituents selectedfrom R⁶, and wherein each said carbocyclyl, aryl, and heterocyclyl areindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁴ is selected from thegroup consisting of hydrogen and —(C₁-C₆)alkyl, and wherein R⁵ isselected from the group consisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidheterocyclyl are optionally substituted with an oxo group, wherein eachsaid (CH₂) moiety may optionally be substituted by one to twosubstituents independently selected substituents selected from R⁶, andwherein each said carbocyclyl, aryl, and heterocyclyl are independentlyoptionally substituted by 1 to 3 substituents selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁴ is hydrogen,and wherein R⁵ is selected from the group consisting of—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀)aryl,—(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl, —(CH₂)_(t)(4 to 14 memberedheterocyclyl), and —(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 memberedheterocyclyl), wherein said heterocyclyl has 1 to 3 ring heteroatomsselected from the group consisting of N, O, and S, and wherein one ortwo carbon atoms of said heterocyclyl are optionally substituted with anoxo group, wherein each said (CH₂) moiety may optionally be substitutedby one to two substituents independently selected from R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidaryl or heterocyclyl are optionally substituted with an oxo group,wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said carbocyclyl, aryl, and heterocyclyl areindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶, and wherein each R⁶ is independently selected from the groupconsisting of azide, halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N,—(C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, andwherein each R⁶ is independently selected from the group consisting ofazide, halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, and wherein R¹ is selected from the group consistingof halo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹].

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, and wherein R² is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, and wherein R^(3A) is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷ and wherein each R^(3B) is independently selected fromthe group consisting of hydrogen, —(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C₁₀ aryl), wherein saidalkyl, carbocyclyl, or aryl may optionally be substituted by one tothree substituents independently selected from the group consisting ofhalo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, andwherein each R⁶ is independently selected from the group consisting ofazide, halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]tOR⁷, and wherein R⁴ is hydrogen.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁶ isindependently selected from the group consisting of azide, halo, —OR⁷,—CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and —[C(R⁷)₂]_(t)OR⁷, and whereineach R⁷ is independently selected from the group consisting of H, —CF₃,and —(C₁-C₆)alkyl, wherein said alkyl may optionally be substituted byone to three substituents independently selected from the groupconsisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, andwherein each R⁶ is independently selected from the group consisting ofazide, halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, and wherein each R⁷ is independently selected from thegroup consisting of H, —CF₃, and —(C₁-C₆)alkyl, wherein said alkyl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—C(═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O and wherein R¹is selected from the group consisting of halo, —(CH₂)_(t)CF₃,—(CH₂)_(t)C≡N, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂, —(CH₂)_(t)R⁹, and—(CH₂)_(t)O[(CH₂)_(t)R⁹].

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O and wherein R²is selected from the group consisting of hydrogen and —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O and wherein Thecompound of Formula I or a pharmaceutically acceptable salt thereofwherein each R^(3A) is independently selected from the group consistingof hydrogen and —(C₁-C₆)alkyl, wherein each said alkyl may optionally besubstituted by one to three substituents independently selected from thegroup consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O and wherein eachR^(3B) is independently selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀ aryl), wherein said alkyl, carbocyclyl, or aryl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂,—S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl,—(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O and wherein R⁴is selected from the group consisting of hydrogen and —(C₁-C₆)alkyl.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein X is O and wherein R⁵is selected from the group consisting of —(CH₂)_(t)(C₃-C₁₂)carbocyclyl,—(CH₂)_(t)(C₆-C₁₀)aryl, —(CH₂)_(t)N[(CH₂)_(t)R⁹](C₆-C₁₀)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), and—(CH₂)_(t)(N[(CH₂)_(t)R⁹])(4 to 14 membered heterocyclyl), wherein saidheterocyclyl has 1 to 3 ring heteroatoms selected from the groupconsisting of N, O, and S, and wherein one or two carbon atoms of saidaryl or heterocyclyl are optionally substituted with an oxo group,wherein each said (CH₂) moiety may optionally be substituted by one totwo substituents independently selected substituents selected from R⁶,and wherein each said carbocyclyl, aryl, and heterocyclyl areindependently optionally substituted by 1 to 3 substituents selectedfrom R⁶.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of:

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, wherein R¹ is selected from the group consisting ofhalo, —(CH₂)_(t)CF₃, —(CH₂)_(t)C≡N, —(CH₂)_(t)N[(CH₂)_(t)R⁹]₂,—(CH₂)_(t)R⁹, and —(CH₂)_(t)O[(CH₂)_(t)R⁹], and wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, wherein R² is hydrogen, and wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, wherein R^(3A) is hydrogen, and wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, whereineach R⁶ is independently selected from the group consisting of azide,halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, wherein each R^(3B) is independently selected from thegroup consisting of hydrogen, —(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —(CH₂)_(t)(C₆-C_(1c), aryl), wherein saidalkyl, carbocyclyl, or aryl may optionally be substituted by one tothree substituents independently selected from the group consisting ofhalo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl, —(C₁-C₆)alkoxy, —CF₃,—OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —(C═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl, and wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, andwherein each R⁶ is independently selected from the group consisting ofazide, halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]M(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, wherein R⁴ is hydrogen, and wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein each R⁶ isindependently selected from the group consisting of azide, halo, —OR⁷,—CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₀)aryl(R⁷),—(CH₂)_(t)(4 to 14 membered heterocyclyl)(R⁷), —(C═O)R⁷,—[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and —[C(R⁷)₂]_(t)OR⁷, wherein eachR⁷ is independently selected from the group consisting of H, —CF₃, and—(C₁-C₆)alkyl, wherein said alkyl may optionally be substituted by oneto three substituents independently selected from the group consistingof halo, hydroxy, —CN, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, —CF₃, —OCF₃,—N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl, —(S═O)(C₁-C₆)alkyl,—S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl, —C(═O)(C₁-C₆)alkyl, and—(C₃-C₁₂)carbocyclyl, and wherein X is O.

In one embodiment the invention relates to a compound of Formula I or apharmaceutically acceptable salt thereof wherein R⁵ is selected from thegroup consisting of

wherein one or two carbon atoms of said aryl are optionally substitutedwith an oxo group, wherein each said (CH₂) moiety may optionally besubstituted by one to two substituents independently selectedsubstituents selected from R⁶, wherein each said aryl is independentlyoptionally substituted by 1 to 3 substituents selected from R⁶, andwherein each R⁶ is independently selected from the group consisting ofazide, halo, —OR⁷, —CF₃, —OCF₃, —(CH₂)_(t)C≡N, —(C₁-C₆)alkyl,—(CH₂)_(t)(C₆-C₁₀)aryl(R⁷), —(CH₂)_(t)(4 to 14 memberedheterocyclyl)(R⁷), —(C═O)R⁷, —[C(R⁷)₂]_(t)N(R⁷)₂, —(CH₂)_(t)SR⁷, and—[C(R⁷)₂]_(t)OR⁷, wherein each R⁷ is independently selected from thegroup consisting of H, —CF₃, and —(C₁-C₆)alkyl, wherein said alkyl mayoptionally be substituted by one to three substituents independentlyselected from the group consisting of halo, hydroxy, —CN, —(C₁-C₆)alkyl,—(C₁-C₆)alkoxy, —CF₃, —OCF₃, —N[(CH₂)_(t)R⁹]₂, —NO₂, —S(C₁-C₆)alkyl,—(S═O)(C₁-C₆)alkyl, —S(═O)₂(C₁-C₆)alkyl, —(C═O)O(C₁-C₆)alkyl,—C(═O)(C₁-C₆)alkyl, and —(C₃-C₁₂)carbocyclyl, and wherein X is O.

In still another embodiment is provided a compound of Formula II(a), orII(b), or II(c), or II(d), or II(e),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^(3B) is hydrogen, (C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₂)aryl, or—(CH₂)_(t)(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

R¹⁰ is —(CH₂)_(t)(C₆-C₁₂)aryl or —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein each of said (C₆-C₁₂)aryl and (4 to 14 memberedheterocyclyl) is optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula II(a), or II(b),or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, Br, —CH₃, —OCH₃, —CF₃, —CN, or —NR¹⁶R¹⁷;

R² is hydrogen;

R^(3B) is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, or —CH₂(phenyl);

R⁴ is hydrogen;

R¹⁰ is phenyl, pyridyl, or 2,3-dihydro-1,4-benzodioxinyl, wherein eachof said phenyl, pyridyl, and 2,3-dihydro-1,4-benzodioxinyl is optionallysubstituted with from 1 to 5 substituents each of which is independentlyselected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷,(C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl),—C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In yet another embodiment is provided a compound of Formula II(a), orII(b), or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or2,3-dihydro-1,4-benzodioxin-6-yl, wherein each of said phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another still embodiment is provided a compound of Formula II(a), orII(b), or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is phenyl, 3-pyridyl, or 2,3-dihydro-1,4-benzodioxin-6-yl, whereineach of said phenyl, 3-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

A further embodiment provides a compound of Formula II(a), or II(b), orII(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃,—OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided herein is a compound of Formula II(a), or II(b), orII(c), or II(d), or II(e),

wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from —CH₃, —CN, —F, —Cl, —Br, —CF₃,—OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula II(a), or II(b),or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula II(a), or II(b),or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from —CH₃, —CN, —F, —Cl, —Br,—CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula II(a), or II(b),or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from(C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂,—(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula II(a), or II(b),or II(c), or II(d), or II(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁰ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from —CH₃,—CN, —F, —Cl, —Br, —CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^(3B) is hydrogen, (C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₂)aryl, or—(CH₂)_(t)(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

R¹¹ is —(CH₂)_(t)(C₆-C₁₂)aryl or —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein each of said (C₆-C₁₂)aryl and (4 to 14 memberedheterocyclyl) is optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, Br, —CH₃, —OCH₃, —CF₃, —CN, or —NR¹⁶R¹⁷;

R² is hydrogen;

R^(3B) is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, or —CH₂(phenyl);

R⁴ is hydrogen;

R¹¹ is phenyl, pyridyl, or 2,3-dihydro-1,4-benzodioxinyl, wherein eachof said phenyl, pyridyl, and 2,3-dihydro-1,4-benzodioxinyl is optionallysubstituted with from 1 to 5 substituents each of which is independentlyselected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷,(C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl),—C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or2,3-dihydro-1,4-benzodioxin-6-yl, wherein each of said phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is phenyl, 3-pyridyl, or 2,3-dihydro-1,4-benzodioxin-6-yl, whereineach of said phenyl, 3-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃,—OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from —CH₃, —CN, —F, —Cl, —Br, —CF₃,—OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from —CH₃, —CN, —F, —Cl, —Br,—CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from(C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂,—(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula III(a), or III(b), or III(c),or III(d), or III(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹¹ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from —CH₃,—CN, —F, —Cl, —Br, —CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

Also provided herein is a compound of Formula IV(a), or IV(b), or IV(c),or IV(d), or IV(e),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^(3B) is hydrogen, (C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₂)aryl, or—(CH₂)_(t)(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

each R¹² is independently selected from —(CH₂)_(t)(C₆-C₁₂)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4;

each t is independently 0, 1, or 2; and

z is 0, 1, 2, 3, 4, or 5; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula IV(a), or IV(b),or IV(c), or IV(d), or IV(e), wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

each R¹² is independently selected from —CN, —F, —Cl, —Br, —CF₃, —OCF₃,—NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

z is 0, 1, 2, 3, 4, or 5; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula IV(a), or IV(b), or IV(c), orIV(d), or IV(e), wherein:

each R¹ is independently halo, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹² is —CN, —F, —Cl, —Br, —CF₃, —OCF₃, —OCH₃, or —NO₂;

n is 0, 1, 2, 3, or 4; and

z is 1; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula IV(a), or IV(b), or IV(c), orIV(d), or IV(e), wherein:

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹² is —CN, —F, —Cl, —Br, or —CF₃;

n is 0; and

z is 1; or

a pharmaceutically acceptable salt thereof.

Further provided is a compound of Formula IV(a), or IV(b), or IV(c), orIV(d), or IV(e), wherein:

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹² is —CN;

n is 0; and

z is 1; or

a pharmaceutically acceptable salt thereof.

Further provided herein is a compound of Formula V(a), or V(b), or V(c),or V(d), or V(e),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^(3B) is hydrogen, (C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₂)aryl, or—(CH₂)_(t)(C₃-C₁₂)carbocyclyl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

each R¹³ is independently selected from —(CH₂)_(t)(C₆-C₁₂)aryl,—(CH₂)_(t)(4 to 14 membered heterocyclyl), (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4;

each t is independently 0, 1, or 2; and

y is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^(3B) is hydrogen, (C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₂)aryl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —C(O)O(C₁-C₆ alkyl) or—C(O)O(C₆-C₁₂)aryl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

R¹⁴ is —(CH₂)_(t)(C₆-C₁₂)aryl or —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein each of said (C₆-C₁₂)aryl and (4 to 14 memberedheterocyclyl) is optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, Br, —CH₃, —OCH₃, —CF₃, —CN, or —NR¹⁶R¹⁷;

R² is hydrogen;

R^(3B) is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, or —CH₂(phenyl);

R⁴ is hydrogen;

R¹⁴ is phenyl, pyridyl, or 2,3-dihydro-1,4-benzodioxinyl, wherein eachof said phenyl, pyridyl, and 2,3-dihydro-1,4-benzodioxinyl is optionallysubstituted with from 1 to 5 substituents each of which is independentlyselected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷,(C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl),—C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or2,3-dihydro-1,4-benzodioxin-6-yl, wherein each of said phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is phenyl, 3-pyridyl, or 2,3-dihydro-1,4-benzodioxin-6-yl, whereineach of said phenyl, 3-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃,—OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from —CH₃, —CN, —F, —Cl, —Br, —CF₃,—OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from —CH₃, —CN, —F, —Cl, —Br,—CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from(C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂,—(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VI(a), or VI(b),or VI(c), or VI(d), or VI(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁴ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from —CH₃,—CN, —F, —Cl, —Br, —CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e),

wherein:

each R¹ is independently halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, —CF₃, —CN,or —NR¹⁶R¹⁷;

R² is hydrogen or (C₁-C₆)alkyl;

R^(3B) is hydrogen, (C₁-C₆)alkyl, —(CH₂)_(t)(C₆-C₁₂)aryl,—(CH₂)_(t)(C₃-C₁₂)carbocyclyl, —C(O)O(C₁-C₆)alkyl, or—C(O)O(C₆-C₁₂)aryl;

R⁴ is hydrogen or (C₁-C₆)alkyl;

R¹⁵ is —(CH₂)_(t)(C₆-C₁₂)aryl or —(CH₂)_(t)(4 to 14 memberedheterocyclyl), wherein each of said (C₆-C₁₂)aryl and (4 to 14 memberedheterocyclyl) is optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, Br, —CH₃, —OCH₃, —CF₃, —CN, or —NR¹⁶R¹⁷;

R² is hydrogen;

R^(3B) is hydrogen, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, or —CH₂(phenyl);

R⁴ is hydrogen;

R¹⁵ is phenyl, pyridyl, or 2,3-dihydro-1,4-benzodioxinyl, wherein eachof said phenyl, pyridyl, and 2,3-dihydro-1,4-benzodioxinyl is optionallysubstituted with from 1 to 5 substituents each of which is independentlyselected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷,(C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl),—C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or2,3-dihydro-1,4-benzodioxin-6-yl, wherein each of said phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is phenyl, 3-pyridyl, or 2,3-dihydro-1,4-benzodioxin-6-yl, whereineach of said phenyl, 3-pyridyl, and 2,3-dihydro-1,4-benzodioxin-6-yl isoptionally substituted with from 1 to 5 substituents each of which isindependently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃,—NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl), and—S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from (C₁-C₆)alkyl, —CN, halo, —CF₃,—OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is phenyl optionally substituted with from 1 to 5 substituents eachof which is independently selected from —CH₃, —CN, —F, —Cl, —Br, —CF₃,—OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from (C₁-C₆)alkyl, —CN, halo,—CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂, —(CH₂)_(t)(C₆-C₁₂)aryl,—C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12 membered heterocyclyl),and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is 3-pyridyl optionally substituted with from 1 to 5 substituentseach of which is independently selected from —CH₃, —CN, —F, —Cl, —Br,—CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from(C₁-C₆)alkyl, —CN, halo, —CF₃, —OCF₃, —NR¹⁶R¹⁷, (C₁-C₆)alkoxy, —NO₂,—(CH₂)_(t)(C₆-C₁₂)aryl, —C(O)(C₁-C₆ alkyl), —C(O)CF₃, azido, (4 to 12membered heterocyclyl), and —S((C₁-C₆)alkyl);

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl;

n is 0, 1, 2, 3, or 4; and

each t is independently 0, 1, or 2; or

a pharmaceutically acceptable salt thereof.

In another embodiment is provided a compound of Formula VII(a), orVII(b), or VII(c), or VII(d), or VII(e), wherein:

each R¹ is independently F, Cl, —CH₃, —OCH₃, —CF₃, —CN, or —N(CH₃)₂;

R² is hydrogen;

R^(3B) is —CH₃;

R⁴ is hydrogen;

R¹⁵ is 2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with from1 to 5 substituents each of which is independently selected from —CH₃,—CN, —F, —Cl, —Br, —CF₃, —OCF₃, —NR¹⁶R¹⁷, —OCH₃, and —NO₂;

each R¹⁶ and R¹⁷ is independently selected from hydrogen and(C₁-C₆)alkyl; and

n is 0, 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

It is specifically contemplated herein that each of Formulae I, II(a),II(b), II(c), II(d), II(e), III(a), III(b), III(c), III(d), III(e),IV(a), IV(b), IV(c), IV(d), IV(e), V(a), V(b), V(c), V(d), V(e), VI(a),VI(b), VI(c), VI(d), VI(e), VII(a), VII(b), VII(c), VII(d), and VII(e)are intended to represent separate embodiments.

In one embodiment the invention relates to a compound of Formula I,wherein said compound is selected from the group consisting of:

-   5-chloro-N-[(2R,4R)-2-(5-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-cyclopropylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-1-cyclobutyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-(6-methylpyridin-3-yl)-3-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}urea;-   1-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[(2R,4R)-1-cyclobutyl-2-(5,6-dimethyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-cyclobutylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-(6-methoxypyridin-3-yl)-3-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}urea;-   1-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   N-[(2R,4R)-2-(5-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carbothioamide;-   1-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-(6-methoxypyridin-3-yl)-3-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]urea;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-5-chloro-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   5-chloro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-1-cyclobutyl-2-(5-methoxy-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(6-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   5-fluoro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(6-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-7-chloro-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   7-chloro-N-[(2R,4R)-2-(5-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   7-chloro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-(4-cyanophenyl)-3-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-cyclobutylpiperidin-4-yl]-3-(4-cyanophenyl)urea;-   1-(4-cyanophenyl)-3-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]urea;-   1-(4-cyanophenyl)-3-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]urea;-   1-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[4-(trifluoromethyl)phenyl]urea;-   1-(4-cyanophenyl)-3-[(2R,4R)-2-(5-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-propylpiperidin-4-yl]-3-(4-cyanophenyl)urea;-   5-chloro-N-[(2R,4R)-2-(5-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-cyclopropylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-chlorophenyl)urea;-   1-[(2R,4R)-1-cyclobutyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[4-chloro-3-(trifluoromethyl)phenyl]urea;-   1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(3,5-dichlorophenyl)urea;-   1-(6-methylpyridin-3-yl)-3-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-ethylpiperidin-4-yl]-3-(4-cyanophenyl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-fluoropyridin-3-yl)urea;-   1-(4-cyanophenyl)-3-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}urea;-   N-[(2R,4R)-1-methyl-2-(6-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-isopropylphenyl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[4-(trifluoromethoxy)phenyl]urea;-   1-[(2R,4R)-2-(6-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea;-   1-[(2R,4R)-1-cyclobutyl-2-(5,6-dimethyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-cyclobutylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-(6-methoxypyridin-3-yl)-3-{(2R,4R)-1-methyl-2-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-fluoro-4H-1,3-benzodioxin-8-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-methoxyphenyl)urea;-   1-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   N-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(6-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)urea;-   1-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   N-[(2R,4R)-2-(5-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-{(2R,4R)-1-methyl-2-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carbothioamide;-   1-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-(6-methoxypyridin-3-yl)-3-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]urea;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]chromane-6-carboxamide;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-isobutylpiperidin-4-yl]-3-(4-cyanophenyl)urea;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-5-chloro-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(6-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(3-cyanophenyl)urea;-   1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methoxypyridin-3-yl)urea;-   1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3S,5S)-5-(6-methoxy-1H-benzimidazol-2-yl)-1-methylpyrrolidin-3-yl]urea;-   N-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-ethylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   N-[(2R,4R)-2-(6-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-[4-(dimethylamino)phenyl]urea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-phenylurea;-   1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(5,6-dimethylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   5-chloro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   N-[(2R,4R)-2-(6-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;-   1-[(2R,4R)-1-cyclobutyl-2-(5-methoxy-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[(2R,4R)-2-(6-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea;-   1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3S,5S)-1-methyl-5-(6-methyl-1H-benzimidazol-2-yl)pyrrolidin-3-yl]urea;    and-   5-fluoro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide;    or

a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound isN-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-cyclopropylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-[(2R,4R)-1-cyclobutyl-2-(5,6-dimethyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-(6-methylpyridin-3-yl)urea,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound isN-[(2R,4R)-2-(5-chloro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxamide,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-[(2R,4R)-2-(5-cyano-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-(4-cyanophenyl)-3-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]urea,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-[(2R,4R)-1-methyl-2-(5-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]urea,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound isN-[(2R,4R)-1-methyl-2-(6-methyl-1H-benzimidazol-2-yl)piperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is5-fluoro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is7-chloro-N-[(2R,4R)-2-(5-methoxy-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-2,3-dihydro-1,4-benzodioxine-6-carboxamide,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-(4-cyanophenyl)-3-[(2R,4R)-2-(5-fluoro-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]urea,or a pharmaceutically acceptable salt thereof.

In one embodiment the invention relates to a compound of Formula Iwherein said compound is1-[(2R,4R)-2-(5,6-dimethyl-1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(6-methylpyridin-3-yl)urea,or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for the treatment ofabnormal cell growth in a mammal comprising administering to said mammalan amount of a compound of Formula I or a pharmaceutically acceptablesalt thereof that is effective in treating abnormal cell growth.

As used herein, the terms “crystalline and non-crystalline forms,”“forms,” or any reference to a compound of Formula I per se (unlessotherwise specified), is meant to include any acceptable crystalline andnon-crystalline freebase, solvate, hydrate, isomorph, polymorph, salt orprodrug thereof.

In one embodiment the abnormal cell growth is cancer.

In one embodiment, the cancer is selected from the group consisting ofbasal cell cancer, medulloblastoma cancer, liver cancer,rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skincancer, cancer of the head or neck, cutaneous or intraocular melanoma,uterine cancer, ovarian cancer, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, prostatecancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of thebladder, cancer of the kidney or ureter, renal cell carcinoma, carcinomaof the renal pelvis, neoplasms of the central nervous system (CNS),primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, or a combination of one or more of the foregoing cancers.

In one embodiment, the present invention relates to a method for thetreatment of cancer solid tumor in a mammal comprising administering tosaid mammal an amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof that is effective in treating said cancer solidtumor.

In one embodiment, the cancer is a solid tumor selected from the groupconsisting of basal cell cancer, medulloblastoma cancer, liver cancer,rhabdomyosarcoma, lung cancer, bone cancer, and pancreatic cancer.

The present invention also relates to a method for the treatment ofabnormal cell growth in a mammal which comprises administering to saidmammal an amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof that is effective in treating abnormal cellgrowth in combination with an anti-tumor agent selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, radiation, cellcycle inhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

The present invention also provides for a pharmaceutical compositioncomprising an effective amount of a compound of Formula I or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention provides a method for making a compound of FormulaI comprising reacting a compound of formula D:

with a substituted benzene-1,2-diamine in the presence of a couplingreagent resulting in the formation of a benzene-1,2-diamine mono amidewhich is then heated to about 100° C. in the presence of an acid such asacetic acid to form a compound of formula F:

The present invention provides methods of preparing compounds of FormulaI, comprising:

(a) treating a compound of Formula D,

(b) with a 1,2-diamine to afford a compound of formula of formula F, and

(c) deprotecting the compound of Formula F.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically-labelled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe Schemes and/or in the Examples and Preparations below, bysubstituting a readily available isotopically-labelled reagent for anon-isotopically-labelled reagent.

The present invention also relates to the pharmaceutically acceptableacid addition salts of the compounds of the invention. The acids whichare used to prepare the pharmaceutically acceptable acid addition saltsof the aforementioned base compounds of this invention are those whichform non toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as, but not limited to, thechloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of the compounds ofthe invention. The chemical bases that may be used as reagents toprepare pharmaceutically acceptable base salts of those compounds of thecompounds of the invention that are acidic in nature are those that formnon-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines.

As used herein, the terms “compound of the invention” and “compounds ofthe invention” are meant to encompass pharmaceutically acceptable saltsof said compounds.

As used herein, the phrases “compound of Formula I” and “compound ofFormula I or a pharmaceutically acceptable salt thereof” includessolvates or hydrates thereof.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.The compounds of the present invention that include a basic moiety, suchas an amino group, may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the invention. Compounds of the compounds ofthe invention having free amino, amido, hydroxy or carboxylic groups canbe converted into prodrugs. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues which are covalently joined through peptidebonds to free amino, hydroxy or carboxylic acid groups of compounds ofthe invention. The amino acid residues include the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters that are covalently bonded to the above substituents ofthe compounds of the invention through the carbonyl carbon prodrugsidechain.

This invention also encompasses compounds of the invention containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the invention(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers. While all stereoisomers are encompassedwithin the scope of our claims, one skilled in the art will recognizethat particular stereoisomers may be preferred. For example, in the casewhere A is a piperidine ring and R^(3A) and R^(3B) are H, preferredcompounds contain the R configuration at the 4 position wherein the—N(R⁴)C(═X)R⁵ moiety is attached as shown below in the structure (i)(note that in ring A, the N atom is labeled as position 1, and the restof the positions are numbered in a counterclockwise manner relative toposition 1). The most preferred compounds when A is a piperidine ringhave the R configuration at the point of attachment to the —N(R⁴)C(═X)R⁵moiety and the R configuration at point of attachment to thebenzimidazole moiety as shown below in the structure (ii).

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of the invention that can beseparated into rotationally restricted isomers.

The term“2-amino-N-[(3R,5S)-5-[5-(phenylmethyl)-1H-benzimidazol-2-yl]-3-pyrrolidinyl]-acetamide”means a compound of the formula:

The term “(C₁-C₆)alkyl”, as used herein means saturated monovalenthydrocarbon radicals containing from one to six carbon atoms, havingstraight or branched moieties.

The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, “carbocyclic,” or“(C₃-C₁₂)carbocyclyl” as used herein means an aliphatic ring systemhaving three to twelve members. The terms “carbocycle”, “carbocyclyl”,“carbocyclo”, or “carbocyclic” whether saturated or partiallyunsaturated, also refers to rings that are optionally substituted. Theterms also include aliphatic rings that are fused to one or morearomatic or non-aromatic rings, such as in a decahydronaphthyl ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring.

As used herein, the term “cycloalkyl” refers to a mono, fused or bridgedbicyclic or tricyclic carbocyclic rings, (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl,norbornyl, adamantanyl, etc.); said rings may optionally containing 1 or2 double bonds. The term “cycloalkyl” also includes spiro cycloalkylgroups, including, without limitation multi-ring systems joined by asingle atom.

The term “alkoxy”, as used herein means O-alkyl groups wherein alkyl isas defined above.

The terms “hydroxyalkyl”, “alkoxyalkyl”, and alkoxycarbonyl”, used aloneor as part of a larger moiety includes both straight and branched chainscontaining one to six carbon atoms.

The term “alkenyl” used alone or as part of a larger moiety shallinclude both straight and branched chains containing two to ten carbonatoms having at least one carbon-carbon double bond. The terms “alkynyl”used alone or as part of a larger moiety shall include both straight andbranched chains containing two to ten carbon atoms having at least onecarbon-carbon triple bond.

The terms “haloalkyl”, ‘haloalkenyl” and haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halo” is used herein interchangeably with theterm “halogen” means F, Cl, Br, or I. Preferred halo groups are F, Cl,and Br.

The term “heteroatom”, means nitrogen, oxygen, or sulfur and includesany oxidized form of nitrogen and sulfur, and the quaternized form ofany basic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 1 to 3 heteroatoms selected fromoxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NOR (as inN-substituted pyrrolidinyl).

“Aryl” and “(C₆-C₁₂)aryl means aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indanyl and the like. The term alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl” as it is used herein, is a group in which an aromaticring is fused to one or more non-aromatic rings, such as in an indanyl,phenanthridinyl, or tetrahydronaphthyl, where the radical or point ofattachment is on the aromatic ring. The term “aryl” also refers to ringsthat are optionally substituted. The term “aryl” may be usedinterchangeably with the term “aryl ring.”

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinincludes aromatic and non-aromatic ring systems having four to fourteenmembers, preferably five to ten, in which one or more ring carbons,preferably one to four, are each replaced by a heteroatom such as N, O,or S, Non-aromatic heterocyclic groups include groups having only 4atoms in their ring system, but aromatic heterocyclic groups must haveat least 5 atoms in their ring system. The heterocyclic groups includebenzo-fused ring systems. Examples of heterocyclic rings include3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl,3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3]-dioxalanyl,[1,3]-dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl,2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl,benzoxanyl, benzo[1,3]dioxine, benzo[1,4]dioxine, benzopyrrolidinyl,benzopiperidinyl, benzoxolanyl, benzothiolanyl,4,5,6,7-tetrahydropyrazol[1,5-alpha]pyridine and benzothianyl.

Also included within the scope of the term “heterocyclyl”, or“heterocyclic”, as it is used herein, is a group in which a non-aromaticheteroatom-containing ring is fused to one or more aromatic ornon-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl,or tetrahydroquinolinyl, where the radical or point of attachment is onthe non-aromatic heteroatom-containing ring.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” whethersaturated or partially unsaturated, also refers to rings that areoptionally substituted.

An example of a 4 membered heterocyclic group is azetidinyl (derivedfrom azetidine). An example of a 5 membered heterocyclic group isthiazolyl and an example of a 10 membered heterocyclic group isquinolinyl.

Examples of non-aromatic heterocyclic groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl.

Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl (N-attached) or imidazol-2-yl (C-attached).

An example of a heterocyclic group wherein 1 or 2 ring carbon atoms aresubstituted with oxo (═O) moieties is 1,1-dioxo-thiomorpholinyl,thienopyridinone, or pyrimidine-2,4-dione. An example of a heterocyclicgroup wherein 1 ring sulfur atom is substituted with 2 oxo (═O) moietiesis tetrahydrothiophenedioxide.

Also included within the scope of the term “heteroaryl”, as it is usedherein, is a group in which a heteroaromatic ring is fused to one ormore aromatic or nonaromatic rings where the radical or point ofattachment is on the heteroaromatic ring. Examples includetetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ringgroups having five to fourteen members. Examples of heteroaryl ringsinclude 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2 5 pyrazolyl,3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl,carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl,quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, orbenzoisoxazolyl.

The term ‘heteroaryl” also refers to rings that are optionallysubstituted. The term “heteroaryl” may be used interchangeably with theterm ‘heteroaryl ring” or the term “heteroaromatic.” An aryl (includingaralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (includingheteroaralkyl and heteroarylalkoxy and the like) group may contain oneor more R⁵ substituents.

When preparing compounds of the invention in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe form of the intermediate compound which provides the bestcombination of features for this purpose. Such features include themelting point, solubility, processability and yield of the intermediateform and the resulting ease with which the product may be purified onisolation.

The invention also relates to methods for making intermediate compoundsthat are useful for making the compounds of the invention.

As noted above, invention also relates to the pharmaceuticallyacceptable salts of the compounds of the invention. Pharmaceuticallyacceptable salts of the compounds of the invention include the acidaddition and base salts thereof. Suitable acid addition salts are formedfrom acids which form non-toxic salts. Non-limiting examples of suitableacid addition salts include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Non-limiting examples of suitable base salts include the aluminium,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).Methods for making pharmaceutically acceptable salts of compounds of theinvention are known to one of skill in the art.

The compounds of the invention may also exist in unsolvated and solvatedforms. Accordingly, the invention also relates to the hydrates andsolvates of the compounds of the invention.

The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol.

The term ‘hydrate’ is employed when said solvent is water. Oneembodiment of a hydrate is one that defines isolated site, channel, ormetal-ion coordinated hydrates—see Polymorphism in Pharmaceutical Solidsby K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated sitehydrates are ones in which the water molecules are isolated from directcontact with each other by intervening organic molecules. In channelhydrates, the water molecules lie in lattice channels where they arenext to other water molecules. In metal-ion coordinated hydrates, thewater molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

The invention also relates to prodrugs of the compounds of theinvention. Thus certain derivatives of compounds of the invention whichmay have little or no pharmacological activity themselves can, whenadministered into or onto the body, be converted into compounds of theinvention having the desired activity, for example, by hydrolyticcleavage. Such derivatives are referred to as “prodrugs”. Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds of theinvention with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some non-limiting examples of prodrugs in accordance with the inventioninclude

(i) where the compound of the invention contains a carboxylic acidfunctionality

(—COOH), an ester thereof, for example, a compound wherein the hydrogenof the carboxylic acid functionality of the compound of Formula I isreplaced by (C₁-C₆)alkyl;

(ii) where the compound of the invention contains an alcoholfunctionality (—OH), an ether thereof, for example, a compound whereinthe hydrogen of the alcohol functionality of the compound of theinvention is replaced by (C₁-C₆)alkanoyloxymethyl; and

(iii) where the compound of the invention contains a primary orsecondary amino functionality (—NH₂ or —NHR where R≠H), an amidethereof, for example, a compound wherein, as the case may be, one orboth hydrogens of the amino functionality of the compound of theinvention is/are replaced by (C₁-C₆)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of the invention may themselves act asprodrugs of other compounds of the invention.

Also included within the scope of the invention are metabolites ofcompounds of the invention, that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include:

(i) where the compound of the invention contains a methyl group, anhydroxymethyl derivative thereof (e.g., —CH₃—>—CH₂OH):

(ii) where the compound of the invention contains an alkoxy group, anhydroxy derivative thereof (e.g., —OH);

(iii) where the compound of the invention contains a tertiary aminogroup, a secondary amino derivative thereof;

(iv) where the compound of the invention contains a secondary aminogroup, a primary derivative thereof (e.g., —NH₂);

(v) where the compound of the invention contains a phenyl moiety, aphenol derivative thereof (e.g., -Ph->-PhOH); and

(vi) where the compound of the invention contains an amide group, acarboxylic acid derivative thereof (e.g., —CONH₂—>COOH).

Compounds of the invention containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Where a compound of theinvention contains an alkenyl or alkenylene group, geometric cis/trans(or Z/E) isomers are possible. Where structural isomers areinterconvertible via a low energy barrier, tautomeric isomerism(‘tautomerism’) can occur. This can take the form of proton tautomerismin compounds of the invention containing, for example, an imino, keto,or oxime group, or so-called valence tautomerism in compounds whichcontain an aromatic moiety. It follows that a single compound mayexhibit more than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof the invention, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or 1-lysine, or racemic, for example, dl-tartrate ordl-arginine.

The term “stereoisomers” refers to compounds that have identicalchemical constitution, but differ with regard to the arrangement oftheir atoms or groups in space. In particular, the term “enantiomers”refers to two stereoisomers of a compound that are non-superimposablemirror images of one another. The terms “racemic” or “racemic mixture,”as used herein, refer to a 1:1 mixture of enantiomers of a particularcompound. The term “diastereomers”, on the other hand, refers to therelationship between a pair of stereoisomers that comprise two or moreasymmetric centers and are not mirror images of one another.

The compounds of the present invention may have asymmetric carbon atoms.The carbon-carbon bonds of the compounds of the present invention may bedepicted herein using a solid line (-), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds from asymmetric carbon atomsis meant to indicate that all possible stereoisomers at that carbon atomare included. The use of either a solid or dotted wedge to depict bondsfrom asymmetric carbon atoms is meant to indicate that only thestereoisomer shown is meant to be included. It is possible thatcompounds of the invention may contain more than one asymmetric carbonatom. In those compounds, the use of a solid line to depict bonds fromasymmetric carbon atoms is meant to indicate that all possiblestereoisomers are meant to be included. The use of a solid line todepict bonds from one or more asymmetric carbon atoms in a compound ofthe invention and the use of a solid or dotted wedge to depict bondsfrom other asymmetric carbon atoms in the same compound is meant toindicate that a mixture of diastereomers is present.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of the invention contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of an alcoholic solvent such as isopropanol, typically from 2% to20%, and from 0 to 5% by volume of an alkylamine, typically 0.1%diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

The invention also relates to methods for the treatment of abnormal cellgrowth in a mammal. In one embodiment the invention relates to a methodfor the treatment of abnormal cell growth in a mammal comprisingadministering to said mammal an amount of a compound of the inventionthat is effective in treating abnormal cell growth.

In another embodiment the abnormal cell growth is cancer.

In another embodiment the cancer is selected from the group consistingof lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers.

The invention also relates to methods for the treatment of cancer solidtumors in a mammal. In one embodiment the invention relates to thetreatment of cancer solid tumor in a mammal comprising administering tosaid mammal an amount of a compound of the invention that is effectivein treating said cancer solid tumor.

In another embodiment the cancer solid tumor is breast, lung, colon,brain, prostate, stomach, pancreatic, ovarian, skin (melanoma),endocrine, uterine, testicular, or bladder.

In another embodiment the invention relates to a method for thetreatment of abnormal cell growth in a mammal which comprisesadministering to said mammal an amount of a compound of the inventionthat is effective in treating abnormal cell growth in combination withan anti-tumor agent selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, radiation, cell cycle inhibitors,enzymes, topoisomerase inhibitors, biological response modifiers,antibodies, cytotoxics, anti-hormones, and anti-androgens.

In one embodiment is provided a method of treating ectodermally-,mesodermally-, or endodermally-derived cancers.

In still another embodiment the invention relates to a pharmaceuticalcomposition for the treatment of abnormal cell growth in a mammalcomprising an amount of a compound of the invention that is effective intreating abnormal cell growth, and a pharmaceutically acceptablecarrier.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention can be prepared by the following generalmethods and by methods described in detail in the Experimental Section.

Compounds claimed herein can be prepared as described in Scheme 1. InStep 1, Compound A, substituted with a carboxylic acid ester and aprotected amine, is reacted with mesylchloride to form the correspondingmesylate of the alcohol which is then displaced with sodium azide andsubsequently reduced under hydrogenation or similar reductive conditionswell known to one skilled in the art. One skilled in the art willrecognize this transformation could alternatively be accomplished inseveral different routes such as oxidation of the alcohol to the ketoneand subsequent reductive amination with a protected amine that is thendeprotected. In Step 2 the amino group attached to Compound B can bereacted with, for example, an activated carboxylic acid, isocyanate orcarbamoyl chloride to produce the compounds of compound C. Thecarboxylic acid may be activated as a carboxylic acid chloride, as amixed anhydride, formed from, for example pivaloyl chloride orisopropylchloroformate, or as an active intermediate such as is formedby treatment of a carboxylic acid with coupling reagents such asN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,propylphosphonic acid anhydride, or other amide forming reagents wellknown to those skilled in the art. Step 2 is best performed in anaprotic solvent such as tetrahydrofuran, 1,4-dioxane ordimethylformamide and at a range of temperatures but generally from roomtemperature to about 80° C. In Step 3 the carboxylic ester can bedeprotected by means known to one skilled in the art. For example, anethyl ester could be saponified with lithium hydroxide, sodium hydroxideor potassium hydroxide in, for example, an alcoholic solvent such asethanol or in a mixture of an organic solvent such as ethanol, methanolor tetrahydrofuran with water. The saponification could be performed ata range of temperatures but generally at from room temperature to about80° C. In Step 4 the carboxylic acid of Compound D is reacted with asubstituted benzene-1,2-diamine in the presence of a coupling reagentsuch as N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,propylphosphonic acid anhydride, or other amide forming reagents wellknown to those skilled in the art. Starting materials are commerciallyavailable, unless otherwise noted in the Examples. The reaction is bestperformed in an aprotic solvent such as tetrahydrofuran, 1,4-dioxane,dimethylformamide, or acetonitrile. The reaction can be performed at arange of temperatures but generally from room temperature to about 80°C. In Step 5 the resulting benzene-1,2-diamine mono amide can then becyclized to form the benzimidazole ring by heating to about 100° C. inthe presence of an acid such as acetic acid, or by treatment withadditional portions of a coupling agent as described above. Subsequentlyin Step 6 the t-butoxycarbonyl protecting group is removed with hydrogenchloride in an appropriate solvent such as 1,4-dioxane, ethyl acetate ormethylene chloride or with trifluoroacetic acid, neat or in anappropriate solvent such as methylene chloride. Step 6 can be performedat a range of temperatures but generally from about 0° C. to roomtemperature. One skilled in the art will recognize that although at-butoxycarbonyl protecting group is shown in Scheme 1, the amine couldbe protected in alternate ways, such as with a benzyloxycarbonyl group,which would be removed by methods known to one skilled in the art. InStep 7 the amine of Compound G can be substituted by reacting with analdehyde and reducing the resulting imine with a reducing agent such assodium cyanoborohydride in a solvent such as methanol at temperaturesranging from about 0° C. to about 80° C. Alternative reducing agentssuch as sodium triacetoxyborohydride can be used as well as others knowto one skilled in the art. Step 7 could also be accomplished by reactingCompound G with an alkylating agent such as methyl iodide withappropriate protection of reactive functionality in Compound G as wouldbe known by one skilled in the art.

As an example, the synthesis of the free base of Example 31 is shown inScheme 2 and is described is more detail below. Protected ester compoundJ, which is commercially available, is allowed to react with a mixtureof methanesulfonyl chloride and 4-N,N-dimethylaminopyridine (DMAP) inpyridine to provide compound K. Compound K is then allowed to react withsodium azide in N,N-dimethylformamide (DMF) to provide azido compound L,which is then reduced using hydrogen and palladium on carbon to affordamino compound M. Reaction of compound M with 4-isocyanatobenzonitrilein tetrahydrofuran (THF) and in the presence of triethylamine affordsurea derivative compound N. The ester in compound N was then saponifiedusing lithium hydroxide in a mixture of THF, methanol, and water toafford the corresponding carboxylic acid compound O. Coupling ofcompound O with 1,2-phenylenediamine usingbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP) as a coupling agent and diisopropylethylamine(DIEA) was performed in DMF to provide amide compound P. Reaction ofcompound P first with acetic acid afforded a BOC-protected indoleintermediate that was then allowed to react with trifluoroacetic acid toremove the BOC group. This further intermediate compound was thenallowed to react with formaldehyde in the presence of sodiumcyanoborohydride to afford final compound Q. Compound Q can be obtainedin free base form or salt form according to methods known to those ofordinary skill in the art. Precursor compounds such as J, andcorresponding stereoisomers, are commercially available or can beprepared according to methods known to those of skill in the art.

As noted above, the compounds of the invention are useful as inhibitorsof SMO.

-   -   Methods for determining the in vitro activity of these compounds        are described below:

Smoothened (SMO)/Sonic Hedgehog (SHh) Transient TranscriptionalActivation Assay

On Day 1, 2×106 C3H10T1/2 cells (ATCC #CCL-226) were split and seeded in12 mL of growth medium Basal Medium Eagle (BME, Invitrogen #21010-046)supplemented with 2 mM L-glutamine (Invitrogen #25030-081), 0.1 units/mLpenicillin and 0.1 μg/mL streptomycin (Invitrogen #15140-122), and 10%Fetal Bovine Serum (FBS, Invitrogen #16140-071) in a T-75 flask (Costar#3376). They were allowed to attach for 4 hours at 37° C., 5% CO₂. Thecells were then transfected using Fugene 6 (Roch #11 814 443 001) in thefollowing reaction: 48 μL Fugene 6 and 745 μL Opti-MEM (Invitrogen#31985-070) were mixed and allowed to sit at room temperature for 5minutes. 8 μg of pGL4.14/mGli(CS) DNA (10× murine Gli response elementsand minimal CS promoter) and 0.5 μg of pEGFP DNA (Clontech) were added,gently mixed and incubated at room temperature for 20 minutes. Thisentire transfection mix was then added to the T-75 flask containing thecells. The cells were incubated at 37° C., 5% CO₂ for 18-24 hours.

On Day 2, the transfected cells were trypsinized and seeded into white96 well plates (Costar #3917) in 100 μL/well of growth medium at aconcentration of 20,000 cells/well. The cells were allowed to recoverfor 4 hours before adding serum starvation medium Dulbecco's ModifiedEagle Medium (DMEM, Invitrogen #21063-029) supplemented with 2 mML-glutamine, 0.1 units/mL penicillin and 0.1 μg/mL streptomycin, and0.5% Calf Serum (CS, Invitrogen #26170-043). The growth media wasaspirated off, and the cells were rinsed with 100 μL of starvationmedia. 95 μL of starvation media was then added to each well. The cellswere incubated for 20 hours at 37° C., 5% CO₂.

On Day 3, cells were dosed with test compounds at a final concentrationranging from 2 μM to 2 nM. Immediately after dosing cells withcompounds, recombinant human sonic hedgehog (SHh, R&D Systems #1845-SH)was add to a final concentration of 250 ng/mL. A 25 μg vial of SHh wasreconstituted with 250 μL PBS/0.1% BSA to give a 100 ng/μL workingstock. This working stock was then diluted 1:20 in starvation media. Thetransfected cells were incubated with compounds and SHh for 20 hours at37° C., 5% CO₂.

Luciferase assays were conducted on Day 4 using Dual-Glo Luciferaseassay system (Promega #E2940) according to Promega's protocol. Briefly,Dual-Glo luciferase reagent was made up and 100 μL were added to eachwell of the 96 well plate containing media. Plates were shaken at roomtemperature for 10 minutes, and then read on TopCount (Perkin-Elmer).The luminescence was recorded.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the invention, as defined above,or a pharmaceutically acceptable salt, solvate, hydrate or prodrugthereof, that is effective in treating abnormal cell growth. In oneembodiment of this method, the abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,multiple myeloma, cancer of the bladder, cancer of the kidney orurethra, renal cell carcinoma, carcinoma of the renal pelvis, neoplasmsof the central nervous system (CNS), primary CNS lymphoma, spinal axistumors, brain stem glioma, pituitary adenoma, medulloblastoma, or acombination of one or more of the foregoing cancers. In one embodimentthe method comprises comprising administering to a mammal an amount of acompound of the invention that is effective in treating said cancersolid tumor. In one embodiment is provided a method of treating solidand liquid tumors in mammal, comprising administering to said mammal acompound or the invention that is effective in treating such tumors. Inone embodiment the solid tumor is breast, lung, colon, brain, prostate,stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine,testicular, and bladder cancer.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

In another embodiment is provided a method for treating multiple myelomain a mammal, comprising administering to said mammal an amount of acompound of the invention that effective in treating multiple myeloma.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate or prodrug thereof, that is effective in treatingabnormal cell growth in combination with an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the invention, as defined above,or a pharmaceutically acceptable salt, solvate, hydrate or prodrugthereof, that is effective in treating abnormal cell growth, and apharmaceutically acceptable carrier. In one embodiment of saidcomposition, said abnormal cell growth is cancer, including, but notlimited to, basal cell carcinoma, lung cancer, bone cancer, pancreaticcancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, colon cancer, breast cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina, carcinomaof the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of theforegoing cancers. In another embodiment of said pharmaceuticalcomposition, said abnormal cell growth is a benign proliferativedisease, including, but not limited to, psoriasis, benign prostatichypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate or prodrug thereof, that is effective in treatingabnormal cell growth in combination with another anti-tumor agentselected from the group consisting of antimetastatic agents, mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, antibodies,cytotoxics, anti-hormones, and anti-androgens. The invention alsocontemplates a pharmaceutical composition for treating abnormal cellgrowth wherein the composition includes a compound of the invention, asdefined above, or a pharmaceutically acceptable salt, solvate, hydrateor prodrug thereof, that is effective in treating abnormal cell growth,and another anti-tumor agent selected from the group consisting ofmitotic inhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, antibodies,cytotoxics, anti-hormones, and anti-androgens. In one embodiment isprovided a method of treating abnormal cell growth in a mammal,comprising administering to said mammal an amount of a compound of theinvention in combination with targeted therapies.

The invention also relates to a method of inhibiting stem cellproduction or stem cell renewal in a mammal, comprising administering acompound of the invention to said mammal in an amount that is effectiveto inhibit stem cell production or stem cell renewal.

The invention also relates to a method of treating erythroid and myeloidblood disorders in a mammal, comprising administering a compound of theinvention to said mammal in an amount that is effective to treat suchblood disorders.

This invention also relates to a method for the treatment of a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the invention,as defined above, or a pharmaceutically acceptable salt, solvate,hydrate or prodrug thereof, that is effective in treating said disorderin combination with one or more anti-tumor agents listed above. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, Paget's disease, humoral hypercalcemia of malignancy,hypercalcemia from tumors metastatic to bone, and osteoporosis inducedby glucocorticoid treatment; coronary restenosis; and certain microbialinfections including those associated with microbial pathogens selectedfrom adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

This invention also relates to a method of (and to a pharmaceuticalcomposition for) treating abnormal cell growth in a mammal whichcomprise an amount of a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, in combinationwith an amount of one or more substances selected from anti-angiogenesisagents, signal transduction inhibitors, and antiproliferative agents,which amounts are together effective in treating said abnormal cellgrowth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of the invention in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), andArcoxia (etoricoxib). Examples of useful matrix metalloproteinaseinhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO96/27583 (published Mar. 7, 1996), European Patent Application No.97304971.1 (filed Jul. 8, 1997), European Patent Application No.99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998),WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13,1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (publishedAug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European PatentPublication 606,046 (published Jul. 13, 1994), European PatentPublication 931,788 (published Jul. 28, 1999), WO 90/05719 (publishedMay 331, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889(published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCTInternational Application No. PCT/IB98/01113 (filed Jul. 21, 1998),European Patent Application No. 99302232.1 (filed Mar. 25, 1999), GreatBritain patent application number 9912961.1 (filed Jun. 3, 1999), U.S.Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat.No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issuedJan. 19, 1999), and European Patent Publication 780,386 (published Jun.25, 1997), all of which are herein incorporated by reference in theirentirety. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds of the present invention are AG-3340, RO 32-3555, RS 13-0830,and the compounds recited in the following list:

-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic    acid;-   3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   (2R,3R)    1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic    acid;-   4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic    acid hydroxyamide;-   (2R,3R)    1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic    acid;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic    acid;-   3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide; and-   3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic    acid hydroxyamide;

and pharmaceutically acceptable salts, solvates and prodrugs of saidcompounds.

VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 (Pfizer Inc.of South San Francisco, Calif., USA), can also be combined with acompound of the invention. VEGF inhibitors are described in, for examplein WO 99/24440 (published May 20, 1999), PCT International ApplicationPCT/1B99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17,1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504(issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat.No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issuedMar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), U.S.Pat. No. 6,653,308 (issued Nov. 25, 2003), WO 99/10349 (published Mar.4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (publishedJun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438(published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO98/02437 (published Jan. 22, 1998), all of which are herein incorporatedby reference in their entirety. Other examples of some specific VEGFinhibitors are IM862 (Cytran Inc. of Kirkland, Wash., USA); Avastin, ananti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco,Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder,Colo.) and Chiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), may be administered incombination with a compound of the invention. Such erbB2 inhibitorsinclude Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors includethose described in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), each of which is herein incorporated by reference in itsentirety. ErbB2 receptor inhibitors useful in the present invention arealso described in U.S. Provisional Application No. 60/117,341, filedJan. 27, 1999, and in United States Provisional Application No.60/117,346, filed Jan. 27, 1999, both of which are herein incorporatedby reference in their entirety. Other erbb2 receptor inhibitors includeTAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties, and some oftyrosine kinase inhibitors have been identified as erbB2 receptorinhibitors. More recently, five European patent publications, namely EP0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun.22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1(published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30,1992), refer to certain bicyclic derivatives, in particular quinazolinederivatives, as possessing anti-cancer properties that result from theirtyrosine kinase inhibitory properties. Also, World Patent Application WO92/20642 (published Nov. 26, 1992), refers to certain bis-mono andbicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitorsthat are useful in inhibiting abnormal cell proliferation. World PatentApplications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (publishedMar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434(published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO98/02438 (published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose. Other patent applications that refer toanti-cancer compounds are World Patent Application WO00/44728 (publishedAug. 3, 2000), EP 1029853A1 (published Aug. 23, 2000), and WO01/98277(published Dec. 12, 2001) all of which are incorporated herein byreference in their entirety.

Other antiproliferative agents that may be used with the compounds ofthe present invention include inhibitors of the enzyme farnesyl proteintransferase and inhibitors of the receptor tyrosine kinase PDGFr,including the compounds disclosed and claimed in the following U.S.patent application Ser. Nos. 09/221,946 (filed Dec. 28, 1998);09/454,058 (filed Dec. 2, 1999); 09/501,163 (filed Feb. 9, 2000);09/539,930 (filed Mar. 31, 2000); 09/202,796 (filed May 22, 1997);09/384,339 (filed Aug. 26, 1999); and 09/383,755 (filed Aug. 26, 1999);and the compounds disclosed and claimed in the following United Statesprovisional patent applications: 60/168,207 (filed Nov. 30, 1999);60/170,119 (filed Dec. 10, 1999); 60/177,718 (filed Jan. 21, 2000);60/168,217 (filed Nov. 30, 1999), and 60/200,834 (filed May 1, 2000).Each of the foregoing patent applications and provisional patentapplications is herein incorporated by reference in their entirety.

A compound of the invention may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present invention include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

A compound of the invention may be applied as a sole therapy or mayinvolve one or more other anti-tumor substances, for example thoseselected from, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, oxaliplatin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil,capecitabine, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred anti-metabolites disclosed in European PatentApplication No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex (tamoxifen) or, for example anti-androgens such as Casodex(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

The compounds of the present invention may be used alone or incombination with one or more of a variety of anti-cancer agents orsupportive care agents. For example, the compounds of the presentinvention may be used with cytotoxic agents, e.g., one or more selectedfrom the group consisting of a camptothecin, irinotecan HCl (Camptosar),edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere),paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate(Gleevac), Erbitux, gefitinib (Iressa), and combinations thereof. Theinvention also contemplates the use of the compounds of the presentinvention together with hormonal therapy, e.g., exemestane (Aromasin),Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar,and combinations thereof. Further, the invention provides a compound ofthe present invention alone or in combination with one or moresupportive care products, e.g., a product selected from the groupconsisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin,Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separatedosing of the individual components of the treatment.

The compounds of the invention may be used with antitumor agents,alkylating agents, antimetabolites, antibiotics, plant-derived antitumoragents, camptothecin derivatives, tyrosine kinase inhibitors,antibodies, interferons, and/or biological response modifiers. In thisregard, the following is a non-limiting list of examples of secondaryagents that may be used with the compounds of the invention.

Alkylating agents include, but are not limited to, nitrogen mustardN-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,mitobronitol, carboquone, thiotepa, ranimustine, nimustine,temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin,bendamustine, carmustine, estramustine, fotemustine, glufosfamide,ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinatedalkylating compounds include but are not limited to, cisplatin,carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin orsatrplatin;

Antimetabolites include but are not limited to, methotrexate,6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) aloneor in combination with leucovorin, tegafur, UFT, doxifluridine,carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1,gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine,clofarabine, decitabine, eflornithine, ethynylcytidine, cytosinearabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed,ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed,triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or forexample, one of the preferred anti-metabolites disclosed in EuropeanPatent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid;

Antibiotics include but are not limited to: aclarubicin, actinomycin D,amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin,elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C,nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,stimalamer, streptozocin, valrubicin or zinostatin;

Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron,anastrozole (Arimidex), doxercalciferol, fadrozole, formestane,anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant,Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), oranti-androgens such as bicalutamide, flutamide, mifepristone,nilutamide, Casodex®(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)and combinations thereof;

Plant derived anti-tumor substances include for example those selectedfrom mitotic inhibitors, for example vinblastine, docetaxel (Taxotere)and paclitaxel;

Cytotoxic topoisomerase inhibiting agents include one or more agentsselected from the group consisting of aclarubicn, amonafide, belotecan,camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan,irinotecan HCl (Camptosar), edotecarin, epirubicin (Ellence), etoposide,exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone,rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, andcombinations thereof;

Immunologicals include interferons and numerous other immune enhancingagents. Interferons include interferon alpha, interferon alpha-2a,interferon, alpha-2b, interferon beta, interferon gamma-1a or interferongamma-n1. Other agents include PF3512676, filgrastim, lentinan,sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002,dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab,imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa),molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin,thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab,oregovomab, pemtumomab, Provenge;

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity. Such agents include krestin, lentinan, sizofuran, picibanil,or ubenimex;

Other anticancer agents include alitretinoin, ampligen, atrasentanbexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride,fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1-asparaginase,procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,tazarotne, TLK-286, Velcade, Tarceva, or tretinoin;

Other anti-angiogenic compounds include acitretin, fenretinide,thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide,combretastatin A-4, endostatin, halofuginone, rebimastat, removab,Revlimid, squalamine, ukrain and Vitaxin;

Platinum-coordinated compounds include but are not limited to,cisplatin, carboplatin, nedaplatin, or oxaliplatin;

Camptothecin derivatives include but are not limited to camptothecin,10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38,edotecarin, and topotecan;

Tyrosine kinase inhibitors are Iressa or SU5416;

Antibodies include Herceptin, Erbitux, Avastin, or Rituximab;

Interferons include interferon alpha, interferon alpha-2a, interferon,alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1;

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth,or differentiation of tissue cells to direct them to have anti-tumoractivity. Such agents include krestin, lentinan, sizofuran, picibanil,or ubenimex; and

Other antitumor agents include mitoxantrone, 1-asparaginase,procarbazine, dacarbazine, hydroxycarbamide, pentostatin, or tretinoin.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The compounds of the present invention are potent inhibitors of SMO, andthus are all adapted to therapeutic use as antiproliferative agents(e.g., anticancer), antitumor (e.g., effective against solid tumors),antiangiogenesis (e.g., stop or prevent proliferationation of bloodvessels) in mammals, particularly in humans. In particular, thecompounds of the present invention are useful in the prevention andtreatment of a variety of human hyperproliferative disorders such asmalignant and benign tumors of the liver, kidney, bladder, breast,gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval,thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, andother hyperplastic conditions such as benign hyperplasia of the skin(e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH). Itis, in addition, expected that a compound of the present invention maypossess activity against a range of leukemias and lymphoid malignancies.

In one embodiment of the present invention cancer is selected from lungcancer, bone cancer, pancreatic cancer, gastric, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, gynecological, rectal cancer, cancer of the anal region,stomach cancer, colon cancer, breast cancer, uterine cancer, carcinomaof the fallopian tubes, carcinoma of the endometrium, carcinoma of thecervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin'sDisease, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, squamous cell, prostatecancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of thebladder, cancer of the kidney or ureter, renal cell carcinoma, carcinomaof the renal pelvis, neoplasms of the central nervous system (CNS),primary CNS lymphoma, spinal axis tumors, brain, pituitary adenoma, or acombination of one or more of the foregoing cancers.

In another embodiment cancer is selected a solid tumor, such as, but notlimited to, breast, lung, colon, brain (e.g., glioblastoma), prostate,stomach, pancreatic, ovarian, skin (melanoma), endocrine, uterine,testicular, and bladder.

The methods of the present invention include the use of small moleculeswhich inhibit Smo, in the regulation of repair and/or functionalperformance of a wide range of cells, tissues and organs, includingnormal cells, tissues, and organs, as well as those having the phenotypeof ptc loss-of-function, hedgehog gain-of-function, or smoothenedgain-of-function. For instance, the subject method has therapeutic andcosmetic applications ranging from regulation of neural tissues, boneand cartilage formation and repair, regulation of spermatogenesis,regulation of smooth muscle, regulation of lung, liver and other organsarising from the primative gut, regulation of hematopoietic function,regulation of skin and hair growth, etc. Moreover, the subject methodscan be performed on cells that are provided in culture (in vitro), or oncells in a whole animal (in vivo). See, for example, PCT publications WO95/18856 and WO 96/17924.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The present invention also provides a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further relates to a pharmaceutical composition of theinvention which comprises mixing a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined with a pharmaceutically acceptable adjuvant, diluent or carrier.

In another embodiment is provided a method of using a compound of any ofFormulae I, II(a), II(b), II(c), II(d), II(e), III(a), III(b), III(c),III(d), III(e), IV(a), IV(b), IV(c), IV(d), IV(e), V(a), V(b), V(c),V(d), V(e), VI(a), VI(b), VI(c), VI(d), VI(e), VII(a), VII(b), VII(c),VII(d), and VII(e), or a pharmaceutically acceptable salt thereof, inthe preparation of a medicament for the treatment of cancer.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of Formula I or a pharmaceutically acceptable salt may bein the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, morepreferably 10 mg to 100 mg.

The present invention also encompasses sustained release compositions.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex® (tamoxifen) or, for example anti-androgens such as Casodex®(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

EXAMPLES

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a Polaris 5 C18-A column, 20×2.0 mm,with a 3.76 minute gradient elution starting at 95% A/5% B (A: 98%water, 2% acetonitrile, 0.01% formic acid; B: 100% acetonitrile, 0.005%formic acid) ending at 100% B with a 1.0 mL/min flow rate. Compoundswere detected by UV absorption and electrospray mass ionization.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Example 1N-((2R,4R)-1-methyl-2-(6-methyl-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

(2R,4S)-1-tert-butyl 2-methyl4-(methylsulfonyloxy)piperidine-1,2-dicarboxylate: (as described in F.Machetti, F. M. Cordero, F. De Sarlo, A. M. Papini, M. C. Alcaro, A.Brandi, Eur. J. Org. Chem. 2004, 2928-2935.)

MsCl (6.61 mL, 85 mmol) was added dropwise at 0° C. to a solution of(2R,4S)-1-tert-butyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (21g, 81 mmol) and DMAP (100 mg, 0.81 mmol) in pyridine (50 mL). Themixture was stirred at room temperature for 5 hours and then wasconcentrated under reduced pressure to remove most solvent. Brine (200mL) was added and extracted with ethyl acetate (2×200 mL). The organiclayer was dried over MgSO₄, filtered and concentrated under reducedpressure to give title compound 26.7 g (98%) as colorless oil. LC-MS:338.1 (t=1.9 min).

(2R,4R)-1-tert-butyl 2-methyl 4-azidopiperidine-1,2-dicarboxylate

NaN₃ (15.8 g, 243 mmol) was added to a solution of (2R,4S)-1-tert-butyl2-methyl 4-(methylsulfonyloxy)piperidine-1,2-dicarboxylate (26.7 g, 81mmol) in dry DMF (100 mL). The mixture was heated at 60° C. for 18hours. Water (300 mL) was added to the reaction mixture and extractedwith ethyl acetate/heptane (2:1) (2×200 mL). The combined organic layerwas washed by brine and dried over MgSO₄, filtered and concentratedunder reduced pressure to give a colorless oil 22.5 g (98%). LC-MS:285.0 (t=2.5 min).

(2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate

(2R,4R)-1-tert-butyl 2-methyl 4-azidopiperidine-1,2-dicarboxylate (22.5g, 79 mmol) was dissolved in methanol (400 mL), Pd/C (10%, 6 g) wasadded, and the apparatus was flushed three times with N₂ and H₂. Thereaction mixture was hydrogenated at a pressure of 50 psi at roomtemperature for 20 hours, filtered through Celite and rinsed withmethanol and then concentrated under reduced pressure to give the amineas a colorless oil 20 g (96%). GC-MS: 258 (t=2.8 min).

(2R,4R)-1-tert-butyl 2-methyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1,2-dicarboxylate

BOP (6.59 g, 14.9 mmol) was added to a solution of2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (2.68 g, 14.9 mmol)and DIEA (5.3 mL, 30 mmol) in DMF (50 mL). Then (2R,4R)-1-tert-butyl2-methyl 4-aminopiperidine-1,2-dicarboxylate (3.5 g, 13.5 mmol) wasadded to the mixture and the resulting solution was stirred at roomtemperature for 18 hours. Water (100 mL) was added to quench thereaction, and extracted with ethyl acetate (2×100 mL), organic layerswere dried over MgSO₄, and concentrated under reduced pressure. Theresidue was purified by Companion (ReadySep, 120 g, silica gel packed)with ethyl acetate/heptane from 20-50% to give the amide as off-whitesolid 5.4 g (95%). LC-MC: 421.2 (t=2.4 min).

(2R,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-2-carboxylicacid

LiOH (1.23 g, 51.4 mmol) was added to a solution of (2R,4R)-1-tert-butyl2-methyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1,2-dicarboxylate(5.4 g, 12.8 mmol) in THF/MeOH/water (3:2:1) (60 mL) and the resultingsolution was stirred at room temperature for 18 hours. 1M HCl solutionwas added to reaction solution to adjust pH to about 3, extracted withethyl acetate (2×100 mL). The organic layers were dried over MgSO₄ andconcentrated to give the acid as a white solid 5.0 g (96%). LC-MS:407.3; 405.3 (t=2.2 min).

(2R,4R)-tert-butyl24(2-amino-4-methylphenyl)carbamoyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxylate

4-Methylbenzene-1,2-diamine (1.65 g, 13.5 mmol)was added to a mixture of(2R,4R)-1-(tert-butoxycarbonyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-2-carboxylicacid (5.0 g, 12 mmol), BOP (5.71 g, 12.9 mmol) and DIEA (4.3 mL, 24.6mmol) in DMF (30 mL), and the resulting solution was stirred at roomtemperature for 8 hours. Water (100 mL) was added to the reactionmixture and then extracted with ethyl acetate (2×100 mL). The organiclayers were dried over MgSO₄ and concentrated to give a red solid.Purification was done by Companion (ReadySep, 120 g, silica gel packed)with methanol/methylenechloride from 1-5% to give the title compound asa brown solid 4.85 g (80%). LC-MS: 511.2 (t=2.4 min).

N-((2R,4R)-1-methyl-2-(6-methyl-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

The (2R,4R)-tert-butyl2-((2-amino-4-methylphenyl)carbamoyl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxylate(4.8 g, 9.4 mmol) was dissolved in acetic acid (10 mL) and stirred at65° C. for 2 hours. The reaction mixture was concentrated under reducedpressure to remove acetic acid. Then TFA (10 mL) was added to theresidue. The resulting solution was stirred at room temperature for 2hours. The reaction mixture was concentrated to remove TFA and did nextreaction without further purification. 37% formaldehyde solution (3.5mL, 47 mmol) in water was added to a solution of the residue in methanol(50 mL) and the reaction mixture was stirred at room temperature for 1hour, then 1M sodium cyanoborohydride in THF (29 mL) was added carefullyat 0° C. The reaction mixture was stirred at room temperature for 18hours and then solvent was evaporated in vacuum. Saturated sodiumbicarbonate solution (100 mL) and ethyl acetate (200 mL) were added andthe mixture was stirred about 30 minutes. The organic layer wasseparated, dried over MgSO₄, and concentrated. Product was purified byCompanion (ReadySep 120 g, silica gel packed) with CH₃OH/CH₂Cl₂ from2%-6-8% to give the title compound as an off-white solid 3.0 g (78%).LC-MS: 407.3, 405.3 (t=1.2 min).

Example 2N-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-cyclopropylpiperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide

Acetic acid (0.075 mL, 1.3 mmol) was added to a solution ofN-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide(50 mg, 0.13 mmol) in methanol (2 mL) and the then(1-ethoxycyclopropoxy)trimethylsilane (138 mg, 1.79 mmol) was added tothe reaction solution and reaction mixture was stirred at roomtemperature for 10 min, then sodium cyanoborohydride (37 mg, 0.59 mmol)was added carefully. The reaction mixture was stirred at 50° C. 24hours. Saturated sodium bicarbonate solution (10 mL) and ethyl acetate(30 mL) were added. The organic layer was separated, dried over MgSO₄,and concentrated. Product was purified by Companion (ReadySep, 12 g,silica gel packed) with CH₃OH/CH₂Cl₂ from 1%-5% to give the namedcompound as a white solid 46 mg (85%). LC-MS: 419.2, 417.3 (t=1.7 min).

Example 31-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-O-3-(6-(trifluoromethyl)pyridin-3-yl)urea

(2R,4R)-1-tert-butyl 2-methyl4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1,2-dicarboxylate

A solution of CDI (345 mg, 2.13 mmol) in THF (10 mL) was added to asolution of (2R,4R)-1-tert-butyl 2-methyl4-aminopiperidine-1,2-dicarboxylate (500 mg, 1.94 mmol) in THF (15 mL)at room temperature. The reaction mixture was stirred at 70° C. for 3hours. Then 6-(trifluoromethyl)pyridin-3-amine (345 mg, 2.13 mmol) wasadded to the mixture and the resulting solution was stirred at 60° C.for 24 hours. Water (50 mL) and ethyl acetate (50 mL) were added to themixture. The organic layer was separated and dried over MgSO₄ andconcentrated under reduced pressure. The purification was done byCompanion (ReadySep, 40 g, silica gel packed) with ethyl acetate/heptanefrom 40-60% to give 10 as a white solid 550 mg (64%). LC-MS: 447.2,445.3 (t=2.5 min).

(2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-2-carboxylicacid

LiOH (118 mg, 4.93 mmol) was added to a solution of (2R,4R)-1-tert-butyl2-methyl4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1,2-dicarboxylate(550 mg, 1.23 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resultingsolution was stirred at room temperature for 18 hours. 1M HCl solutionwas added to reaction solution to adjust the pH to about 3, extractedwith ethyl acetate (2×50 mL). The organic layers were dried over MgSO₄and concentrated to give the acid as a white solid 500 mg (94%). LC-MS:433.2, 431.3; (t=2.1 min.)

(2R,4R)-tert-butyl2((2-aminophenyl)carbamoyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1-carboxylate

Benzene-1,2-diamine (131 mg, 1.21 mmol)was added to a mixture of(2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-2-carboxylicacid (500 mg, 1.16 mmol), BOP (563 mg, 1.27 mmol) and DIEA (0.403 mL,2.31 mmol) in DMF (5 mL), and the resulting solution was stirred at roomtemperature for 8 hours. Water (20 mL) was added to the reaction mixtureand then extracted with ethyl acetate(2×30 mL). The organic layers weredried over MgSO₄ and concentrated to give a red solid. Purification wasdone by Companion (ReadySep, 40 g, silica gel packed) withmethanol/methylenechloride from 1-5% to give the title compound as awhite solid 550 mg (91%). LC-MS: 523.3, 521.3; (t=2.3 min).

1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)urea

(2R,4R)-tert-butyl2-((2-aminophenyl)carbamoyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1-carboxylate(550 mg, 1.05 mmol) was dissolved in acetic acid (5 mL) and stirred at65° C. for 2 hours. The reaction mixture was concentrated under reducedpressure to remove acetic acid. Then TFA (3 mL) was added to theresidue. The resulting solution was stirred at room temperature for 2hours. The reaction mixture was concentrated to remove TFA and did nextreaction without further purification. 37% formaldehyde solution (0.25mL, 3.2 mmol) in water was added to a solution of the residue inmethanol (5 mL) and the reaction mixture was stirred at room temperaturefor 1 hour, then 1M sodium cyanoborohydride in THF (3.2 mL, 3.2 mmol)was added carefully at 0° C. The reaction mixture was stirred at roomtemperature for 18 hours and then solvent was evaporated in vacuum.Saturated sodium bicarbonate solution (20 mL) and ethyl acetate (40 mL)were added and the mixture was stirred about 30 min. The organic layerwas separated and dried over MgSO₄, and concentrated. Product waspurified by Companion (ReadySep 40 g, silica gel packed) withCH₃OH/CH₂Cl₂ from 2%-6-8% to give the title compound as an off-whitesolid 270 mg (52%). LC-MS: 419.2, 417.3 (t=1.7 min).

Example 41-(4-cyanophenyl)-3-((2R,4R)-2-(5,6-dimethyl-1H-benzo[d]imidazol-2-O-1-methylpiperidin-4-yl)urea

(2R,4R)-1-tert-butyl 2-methyl4-(3-(4-cyanophenyl)ureido)piperidine-1,2-dicarboxylate

4-isocyanatobenzonitrile (1.17 g, 8.13 mmol) was added to a solution of(2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate (2.0g, 7.7 mmol) and NEt₃ (1.3 mL, 9.3 mmol) in THF (30 mL), and theresulting solution was stirred at room temperature for 6 hours. 1Mammonia in methanol (5 mL) was added to reaction mixture to quenchexcess isocyanine. Water (100 mL) and ethyl acetate (200 mL) were addedto the mixture. The organic layer was separated and dried over MgSO₄ andconcentrated to give a solid. Purification was done by Companion(ReadySep, 80 g, silica gel packed) with ethyl acetate/heptane from40-70% to give the urea as a white solid 2.9 g (90%). LC-MS: 403.2,401.3 (t=2.6 min).

(2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylicacid

LiOH (143 mg, 5.96 mmol) was added to a solution of (2R,4R)-1-tert-butyl2-methyl 4-(3-(4-cyanophenyl)ureido)piperidine-1,2-dicarboxylate (1200mg, 2.98 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resultingsolution was stirred at room temperature for 18 hours. 1M HCl solutionwas added to reaction solution to adjust pH to about 3, extracted withethyl acetate (2×50 mL). The organic layers were dried over MgSO₄ andconcentrated to give the acid as a white solid 1150 mg (99%). LC-MS:389.2, 387.3 (t=2.1 min).

(2R,4R)-tert-butyl2-((2-amino-4,5-dimethylphenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate

4,5-dimethylbenzene-1,2-diamine (39 mg, 0.286 mmol)was added to amixture of(2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylicacid (100 mg, 0.258 mmol), BOP (120 mg, 0.27 mmol) and DIEA (0.09 mL,0.52 mmol) in DMF (1 mL), and the resulting solution was stirred at roomtemperature for 8 hours. Water (10 mL) was added to the reaction mixtureand then extracted with ethyl acetate (2×20 mL). The organic layers weredried over MgSO₄ and concentrated to give a red solid. Purification wasdone by Companion (ReadySep, 12 g, silica gel packed) with ethylacetate/heptane from 50-80% to give the title compound as a white solid104 mg (80%). LC-MS: 507.3, 505.4 (t=2.4 min).

1-(4-cyanophenyl)-3-((2R,4R)-2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)urea

(2R,4R)-tert-butyl2-((2-amino-4,5-dimethylphenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate(104 mg, 0.205 mmol) was dissolved in acetic acid (1 mL) and stirred at65° C. for 2 hours. The reaction mixture was concentrated under reducedpressure to remove acetic acid. Then TFA (1 mL) was added to theresidue. The resulting solution was stirred at room temperature for 2hours. The reaction mixture was concentrated to remove TFA and did nextreaction without further purification. 37% formaldehyde solution (0.046mL, 0.616 mmol) in water was added to a solution of the residue inmethanol (2 mL) and the reaction mixture was stirred at room temperaturefor 1 hour, then 1M sodium cyanoborohydride in THF (0.62 mL, 0.62 mmol)was added carefully at 0° C. The reaction mixture was stirred at roomtemperature for 18 hours and then solvent was evaporated in vacuum.Saturated sodium bicarbonate solution (5 mL) and ethyl acetate (20 mL)were added and the mixture was stirred about 30 min. The organic layerwas separated and dried over MgSO₄, and concentrated. Product waspurified by Companion (ReadySep 12 g, silica gel packed) withCH₃OH/CH₂Cl₂ from 1-5% to give the title compound as an off-white solid71 mg (73%). LC-MS: 403.3, 401.4 (t=1.8 min).

Example 5

(2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate

To a solution of (2R,4R)-tert-butyl2-(1H-benzo[d]imidazol-2-yl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxylate(200 mg, 0.418 mmol) in DMF (2 mL) was added2-(2-bromoethoxy)-tetrahydro-2H-pyran (114 mg, 0.543 mmol) and K₂CO₃(116 mg, 0.836 mmol), and the reaction mixture was stirred at 80° C. forover night. Water and ethyl acetate were added to the mixture, organiclayer was separated and dried over MgSO₄ and concentrated. The residuewas purified by HPLC with 0.1% HCOOH in water/0.1% HCOOH in ACN from45-70% to give the named compound as white solid 90 mg (35%). LC-MS:607.2 (t=2.9 min).

(2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate

(2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate(90 mg, 0.15 mmol) was added to a solution of acetic acid (2 mL), THF (1mL) and water (0.5 mL) (4:2:1), the resulting solution was stirred at45° C. for over night. The reaction mixture was concentrated to give ayellow oil as title compound (LC-MS: 523.2, t=2.3 min) for the nextreaction without further purification.

(2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(methylsulfonyloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate

Methanesulfonyl chloride (51.3 mg, 0.448 mmol) was added to a solutionof (2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate(78 mg, 0.15 mmol) and DMAP (3.5 mg) in pyridine (1 mL) at 0° C. and theresulting mixture was stirred at room temperature for 5 hours. Water andethyl acetate were added to the reaction mixture. The organic layer wasseparated and dried over MgSO₄ and concentrated to give a yellow solid,which was purified by Companion (ReadSep, 12 g, silica gel packed) withethyl acetate/heptane from 30-70% to give title compound as a whitesolid 65 mg (73%). LC-MS: 601.1 (t=2.6 min).

(2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate

(2R,4R)-tert-butyl4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-(methylsulfonyloxy)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate(65 mg, 0.11 mmol) was dissolved in TFA (1 mL) and stirred at roomtemperature for 2 hours. The reaction mixture was concentrated toremoved TFA, the residue was dissolved in DMF (1 mL) and K₂CO₃ (30 mg,0.22 mmol) was added to it, the resulting mixture was stirred at 60° C.for over night. Water and ethyl acetate were added to reaction mixture,the organic layer was separated and dried over MgSO₄ and concentrated.Purification was done by Companion (ReadSep, 12 g, silica gel packed)with CH₃OH/CH₂Cl₂ from 1-5% to give a white solid 30 mg (60%) as titlecompound. LC-MS: 405.2 (t=1.4 min).

Free Base of Example 31

(2R,4R)-1-tert-butyl 2-methyl4-(3-(4-cyanophenyl)ureido)piperidine-1,2-dicarboxylate

4-isocyanatobenzonitrile (1.17 g, 8.13 mmol) was added to a solution of(2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate (2.0g, 7.7 mmol) and NEt₃ (1.3 mL, 9.3 mmol) in THF (30 mL), and theresulting solution was stirred at room temperature for 6 hours. 1Mammonia in methanol (5 mL) was then added to the reaction mixture toquench excess isocyanine. Water (100 mL) and ethyl acetate (200 mL) wereadded to the mixture. The organic layer was separated and dried overMgSO₄ and concentrated to give a solid. Purification by Companion(ReadySep, 80 g, silica gel packed) using ethyl acetate/heptane from40-70% as eluent provided the title compound as a white solid 2.9 g(90%). LC-MS: 403.2, 401.3 (t=2.6 min).

(2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylicacid

LiOH (143 mg, 5.96 mmol) was added to a solution of (2R,4R)-1-tert-butyl2-methyl 4-(3-(4-cyanophenyl)ureido)piperidine-1,2-dicarboxylate (1200mg, 2.98 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resultingsolution was stirred at room temperature for 18 hours. 1M HCl solutionwas added to reaction solution to adjust the pH to about 3, the mixturewas then extracted with ethyl acetate (2×150 mL), and the combinedorganic layers were dried over MgSO₄ and concentrated to give the acidas a white solid 1150 mg (99%). LC-MS: 389.2, 387.3 (t=2.1 min).

(2R,4R)-tert-butyl2-((2-amino-phenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate

Benzene-1,2-diamine (365 mg, 3.38 mmol) was added to a mixture of(2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(4-cyanophenyl)ureido)piperidine-2-carboxylicacid (1400 mg, 3.60 mmol), BOP (1600 mg, 3.6 mmol) and DIEA (1.2 mL, 6.9mmol) in DMF (20 mL), and the resulting solution was stirred at roomtemperature for 8 hours. Water (100 mL) was added to the reactionmixture and it was then extracted with ethyl acetate (2×200 mL). Theorganic layers were dried over MgSO₄ and concentrated to give a redsolid. Further purification by Companion (ReadySep, 80 g, silica gelpacked) using ethyl acetate/heptane from 50-80% as eluent provided thetitle compound as a white solid 1600 mg (93%). LC-MS: 479.1, 477.2(t=2.3 min).

1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea

(2R,4R)-tert-butyl2-((2-amino-phenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate(1600 mg, 3.34 mmol) was dissolved in acetic acid (10 mL) and stirred at65° C. for 2 hours. The reaction mixture was concentrated under reducedpressure to remove acetic acid. Trifluoroacetic acid (10 mL) was addedto the residue. The resulting solution was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated to remove TFA and theresulting product was used in the next step without furtherpurification. 37% formaldehyde solution (1.24 mL, 16.7 mmol) in waterwas added to a solution of the residue in methanol (20 mL) and thereaction mixture was stirred at room temperature for 1 hour, then 1Msodium cyanoborohydride in THF (10.5 mL, 10.5 mmol) was added at 0° C.The reaction mixture was stirred at room temperature for 18 hours andthe solvent was evaporated under vacuum. Saturated sodium bicarbonatesolution (50 mL), water (100 mL) and ethyl acetate (200 mL) were addedand the mixture was stirred about 30 min. The organic layer wasseparated, dried over MgSO₄, and concentrated. The resulting product waspurified by Companion (ReadySep 40 g, silica gel packed) usingCH₃OH/CH₂Cl₂ from 1-5% as eluent to provide the title compound as anoff-white solid 915 mg (73%). LC-MS: 375.3, 373.3 (t=1.5 min). ¹H NMR(acetone-D6): δ 1.81 (m, 2H), 1.9-2.05 (m, 2H), 2.10 (m, 1H), 2.17 (s,3H), 2.52 (m, 1H), 2.94 (m, 1H), 3.86 (m, 1H), 4.2 (m, 1H), 6.4 (d, 1H),7.16 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.62 (m, 2H), 8.46 (s, 1H).

Examples listed in the following table were prepared using proceduresanalogous to those described above. In the following table, thestructures are shown; if a salt is associated it is identified in the“Compound Name” column.

SMO CELL % INHIBI- EX. COMPOUND TION @ ANALYTICAL EX # # NAME STRUCTURE2 μM DATA PREP  6 2,3-Dihydro- benzo[1,4]dioxine- 6-carboxylic acid[1-methyl-2-(6- methyl-1H- benzoimidazol-2- yl)-piperidin-4-yl]- amidehydrochloride

105.26 (acetone-D6) δ 1.97 (m, 2H), 2.16 (m, 5H), 2.40 (s, 3H), 2.62 (m,1H), 2.92 (m, 1H), 3.90 (m, 1H), 4.24 (m, 4H), 4.41 (m, 1H), 6.8 (m,1H), 6.97 (m, 1H), 7.16 (s, 1H), 7.40 (m, 3H), 7.52 (d, 1H); HPLC Rt =1.2 MS: [M + H] = 407.3 1  7 1-(4-cyanophenyl)- 3-{(2R,4R)-1-methyl-2-[5- (trifluoromethyl)- 1H-benzimidazol- 2-yl]piperidin-4-yl}urea hydrochloride

109.08 HPLC Rt = 2.0 MS: [M + H] = 443.2 4  8 tert-butyl (2S,4S)- 2-(1H-benzimidazol-2-yl)- 4-[({[4-chloro-3- (trifluoromethyl) phenyl]amino}carbonyl)amino] pyrrolidine-1- carboxylate

 57.10 (CD₃OD) δ 1.42 (s, 9H), 2.54 (m, 1H), 2.88 (m, 1H), 3.58 (m, 1H),3.64 (m, 1H), 4.58 (m, 1H), 5.25 (m, 1H), 7.21-7.30 (m, 4H), 7.35- 7.45(m, 3H), 7.60 (d, 2H), 7.70 (d, 1H) HPLC Rt = 2.62 MS: [M + H] = 524.4 4 9 N-[(3S,5S)-5-(1H- benzimidazol-2- yl)pyrrolidin-3-yl]-2,3-dihydro-1,4- benzodioxine-6- carboxamide

 65.00 HPLC Rt = 1.4 MS: [M + H] = 365 1  10 benzyl (2S,4S)-2-(1H-benzimidazol- 2-yl)-4-[(2,3- dihydro-1,4- benzodioxin-6-ylcarbonyl)amino] pyrrolidine-1- carboxylate

106.29 HPLC Rt = 2.34 MS: [M + H] = 499.3 1  11 N-[(3S,5S)-5-(1H-benzimidazol-2- yl)pyrrolidin-3-yl]- 2,3-dihydro-1,4- benzodioxine-6-carboxamide

110.10 HPLC Rt = 1.67 MS: [M + H] = 365.2 1  12 N-[(2R,13bR)-1,3,4,6,7,13b- hexahydro-2H- pyrido[2′,1′:3,4] pyrazino[1,2-a]benzimidazol-2- yl]-2,3-dihydro-1,4- benzodioxine-6- carboxamidehydrochloride

 64.10 (CD₃OD) δ 1.97 (m, 1H), 2.11 (m, 2H), 2.8 (m, 1H), 2.85 (d, 1H),2.92 (m, 1H), 3.20 (dd, 1H), 3.70 (d, 3H), 4.06 (m, 1H), 4.18 (m, 1H),4.2 (m, 4H), 4.38 (m, 1H), 6.42 (d, 1H), 6.85 (d, 1H), 7.20-7.40 (m,5H), 7.68 (m, 1H) HPLC Rt = 1.4 MS: [M + H] = 405.2 5  13 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3S,5S)- 5-(6-fluoro-1H- benzimidazol-2-yl)pyrrolidin-3- yl]urea

 84.20 HPLC Rt = 2.3 MS: [M + H] = 442.2 4  14 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3R,5S)- 5-(6-fluoro-1H-benzimidazol-2-yl)- 1-methylpyrrolidin- 3-yl]urea

 81.80 HPLC Rt = 2.2 MS: [M + H] = 456 4  15 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[4- (trifluoromethoxy)phenyl]urea hydrochloride

111.40 HPLC Rt = 2 MS: [M + H] = 434.1 4  16 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl)-3-pyridin-4- ylureahydrochloride

110.60 HPLC Rt = 1.5 MS: [M + H] = 351.2 3  17 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3R,5S)- 1-methyl-5-(6- methyl-1H-benzimidazol-2- yl)pyrrolidin-3- yl]urea

 63.20 HPLC Rt = 2.3 MS: [M + H] = 452 4  18 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[4- (trifluoromethyl)phenyl]urea hydrochloride

109.90 HPLC Rt = 1.8 MS: [M + H] = 418.1 4  19 1-[(2R,4R)-2-(5-cyano-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(4-cyanophenyl)urea hydrochloride

109.48 HPLC Rt = 1.6 MS: [M + H] = 400.2 4  20 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3S,5S)- 5-(6-methoxy-1H- benzimidazol-2-yl)pyrrolidin-3- yl]urea

 63.00 HPLC Rt = 2.13 MS: [M + H] = 454 4  21 N-[(3S,5S)-5-(1H-benzimidazol-2-yl)- 1-methylpyrrolidin- 3-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide

 61.80 (CD₃OD) δ 2.10 (m, 1H), 2.18 (s, 3H), 2.78 (m, 1H), 2.82 (m, 1H),3.10 (d, 1H), 3.82 (m, 1H), 4.10 (m, 4H), 4.78 (m, 1H), 6.80 (d, 1H),7.21 (m, 3H), 7.38 (m, 1H), 7.42 (s, 2H), 7.55 (b, 1H), 8.3 (d, 1H) HPLCRt = 1.64 MS: [M + H] = 379.2 1  22 1-[4-chloro-3- (trifluoromethyl)phenyl]-3-[(3S,5S)- 1-methyl-5-(6- methyl-1H- benzimidazol-2-yl)pyrrolidin-3- yl]urea

101.87 HPLC Rt = 2.3 MS: [M + H] = 452 4  23 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3R,5S)- 1-isopropyl-5-(6- methyl-1H-benzimidazol-2- yl)pyrrolidin-3- yl]urea

100.50 HPLC Rt = 2.4 MS: [M + H] = 480 4  24 tert-butyl (2S,4R)- 2-(1H-benzimidazol-2-yl)- 4-[({[4-chloro-3- (trifluoromethyl) phenyl]amino}carbonyl)amino] pyrrolidine-1- carboxylate

 63.10 HPLC Rt = 2.4 MS: [M + H] = 524 4  25 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3S,5S)- 5-(6-methoxy-1H-benzimidazol-2-yl)- 1-methylpyrrolidin- 3-yl]urea

105.02 HPLC Rt = MS: [M + H] = 468 4  26 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[4-chloro-3-(trifluoromethyl) phenyl]urea hydrochloride

108.61 HPLC Rt = 2.0 MS: [M + H] = 452 4  27 N-{(2R,4R)-2-[5-(dimethylamino)- 1H-benzimidazol- 2-yl]-1- methylpiperidin-4-yl}-2,3-dihydro-1,4- benzodioxine-6- carboxamide hydrochloride

108.32 HPLC Rt = 1.3 MS: [M + H] = 436.1 1  28 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(3,5- dichlorophenyl)urea hydrochloride PGP

108.16 HPLC Rt = 2.0 MS: [M + H] = 418 4  29 1-(4-cyanophenyl)-3-[(2R,4R)-2-(5- methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]urea hydrochloride

108.08 HPLC Rt = 1.6 MS: [M + H] = 405.3 4  30 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(4- chlorophenyl)ureahydrochloride

107.88 HPLC Rt = 1.8 MS: [M + H] = 384.1 4  31 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(4- cyanophenyl)ureahydrochloride

107.27 (acetone-D6) δ 1.81 (m, 2H), 1.9- 2.05 (m, 2H), 2.10 (m, 1H),2.17 (s, 3H), 2.52 (m, 1H), 2.94 (m, 1H), 3.86 (m, 1H), 4.2 (m, 1H), 6.4(d, 1H), 7.16 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.62 (m, 2H), 8.46(s, 1H) HPLC Rt = 1.3 MS: [M + H] = 375.4 4  32 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6- fluoropyridin-3-yl)urea hydrochloride

107.12 HPLC Rt = 1.8 MS: [M + H] = 369.2 3  33 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]chromane-6- carboxamidehydrochloride

114.00 HPLC Rt = 1.6 MS: [M + H] = 391.3 1  34 N-[(2R,4R)-2-(6-chloro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

107.04 HPLC Rt = 1.7 MS: [M + H] = 427.2 1  35 1-{(2R,4R)-1-methyl-2-[5- (trifluoromethyl)- 1H-benzimidazol- 2-yl]piperidin-4-yl}-3-[6- (trifluoromethyl) pyridin-3-yl]urea hydrochloride

106.98 HPLC Rt = 2.2 MS: [M + H] = 487.2 3  36 1-(4-cyanophenyl)-3-[(2R,4R)-1- methyl-2-(5- methyl-1H- benzimidazol-2- yl)piperidin-4-yl]urea hydrochloride

106.56 HPLC Rt = 1.6 MS: [M + H] = 389.3 4  37 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(4- methoxyphenyl) ureahydrochloride

106.48 HPLC Rt = 1.8 MS: [M + H] = 380.1 4  38 N-[(2R,4R)-2-(6-methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

106.03 (CD₃OD) δ 1.97 (m, 2H), 2.11 (m, 2H), 2.1 (s, 3H), 2.42 (m, 1H),2.92 (m, 1H), 3.70 (m, 1H), 3.80 (s, 3H), 4.24 (m, 4H), 4.38 (m, 1H),6.24 (d, 1H), 6.85 (m, 2H), 7.0 (b, 1H), 7.12 (m, 2H), 7.15 (s, 1H), 7.4(b, 1H) HPLC Rt = 1.3 MS: [M + H] = 423.3 1  39 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-isobutylpiperidin- 4-yl]-3-(4- cyanophenyl)urea

105.90 1H NMR (CD₃OD, 400 MHz) δ 0.73 (d, 3H), 0.82 (d, 3H), 1.75 (m,1H), 1.82 (m, 1H), 1.92 (m, 1H), 2.00 (m, 1H), 2.04 (m, 1H), 2.10 (m,1H), 2.20 (m, 1H), 2.38 (m, 1H), 3.10 (m, 1H), 3.79 (m, 1H), 4.08 (m,1H), 7.21 (dd, 2H), 7.50-7.60 (m, 4H), 7.62 (d, 2H); HPLC Rt = 2.6 MS:[M + H] = 417 4  40 1-[(2R,4R)-2-(1H- benzimidazol-2-yl)-1-methylpiperidin- 4-yl]-3-(6-fluoro-5- methylpyridin-3- yl)ureahydrochloride

105.85 HPLC Rt = 1.3 MS: [M + H] = 383.3 3  41 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6-fluoro- 4H-1,3-benzodioxin-8- yl)urea hydrochloride

105.81 HPLC Rt = 1.5 MS: [M + H] = 426.3 4  42 N-[(2S,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

105.67 HPLC Rt = 1.5 MS: [M + H] = 393 1  43 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(5- cyanopyridin-2-yl)urea hydrochloride

105.51 HPLC Rt = 2.0 MS: [M + H] = 376.2 3  44 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-ethylpiperidin-4- yl]-2,3-dihydro-1,4-benzodioxine-6- carboxamide hydrochloride

105.48 HPLC Rt = 1.5 MS: [M + H] = 407.2 1  45 N-[(2R,4R)-2-(6-fluoro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

105.47 (CD₃OD) δ 1.97 (m, 2H), 2.15 (m, 2H), 2.2 (s, 3H), 2.46 (m, 1H),2.92 (m, 1H), 3.70 (m, 1H), 4.24 (m, 4H), 4.38 (m, 1H), 6.24 (d, 1H),6.85 (m, 1H), 7.0 (m, 1H), 7.22 (m, 2H), 7.3 (s, 1H), 7.4 (b, 1H) HPLCRt = 1.41 MS: [M + H] = 411.3 1  46 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-ethylpiperidin-4- yl]-3-(4- cyanophenyl)urea

105.42 ¹H NMR (CD₃OD, 400 MHz) δ 1.04 (t, 3H), 1.86 (m, 1H), 2.04 (m,2H), 2.14 (m, 1H), 2.27 (m, 1H), 2.49 (m, 2H), 3.14 (m, 1H), 3.90 (m,1H), 4.11 (m, 1H), 7.21 (dd, 2H), 7.49-7.62 (m, 6H); HPLC Rt = 2.5 MS:[M + H] = 389 4  47 N-[(2R,4R)-2-(1H- benzimidazol-2-yl)-1-methylpiperidin- 4-yl]-2,3-dihydro-1- benzofuran-5- carboxamidehydrochloride

105.41 HPLC Rt = 1.31 MS: [M + H] = 377.3 1  48 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(2,6- dimethylpyridin-3-yl)urea hydrochloride

105.32 HPLC Rt = 1.5 MS: [M + H] = 379.3 3  49 N-[(2R,4R)-2-(5,6-dimethyl-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

105.29 HPLC Rt = 1.5 MS: [M + H] = 421.3 1  50 4-acetyl-N-[(2R,4R)-2-(1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]-3,5-dimethyl- 1H-pyrrole-2- carboxamide hydrochloride

105.07 HPLC Rt = 1.3 MS: [M + H] = 394.3 1  51 1-(4-cyanophenyl)-3-[(2R,4R)-2-(5- fluoro-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]urea hydrochloride

105.02 HPLC Rt = 1.6 MS: [M + H] = 393.2 4  52 1-(4-cyanophenyl)-3-[(2R,4R)-2-(5,6- dimethyl-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]urea hydrochloride

104.97 HPLC Rt = 1.8 MS: [M + H] = 403.3 4  53 1-[(2R.4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(4- isopropylphenyl) ureahydrochloride

104.80 HPLC Rt = 2.1 MS: [M + H] = 392.4 4  54 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6- cyanopyridin-3-yl)urea hydrochloride

104.76 HPLC Rt = 1.3 MS: [M + H] = 376.2 4  55 1-[(2R,4R)-2-(5-cyano-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[6-(trifluoromethyl) pyridin-3-yl]urea hydrochloride

104.54 HPLC Rt = 1.8 MS: [M + H] = 444.2 3  56 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[4- (dimethylamino)phenyl]urea hydrochloride

104.46 HPLC Rt = 1.14 MS: [M + H] = 393.4 4  57 N-[(2R,4R)-2-(5,6-difluoro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

104.42 HPLC Rt = 1.8 MS: [M + H] = 429.4 1  58 1-[4-chloro-3-(trifluoromethyl) phenyl]-3-[(3S,5S)- 5-(6-fluoro-1H-benzimidazol-2-yl)- 1-methylpyrrolidin- 3-yl]urea

104.39 HPLC Rt = 2.3 MS: [M + H] = 456 4  59 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-propylpiperidin- 4-yl]-3-(4- cyanophenyl)urea

104.25 ¹H NMR (CD₃OD, 400 MHz) δ 0.78 (t, 3H), 1.5 (m, 3H), 1.82 (m,1H), 2.04 (m, 2H), 2.21 (m, 2H), 2.37 (m, 1H), 2.55 (m, 1H), 3.18 (m,1H), 3.95 (m, 1H), 7.21 (dd, 2H), 7.49-7.62 (m, 6H); HPLC Rt = 2.5 MS:[M + H] = 403 4  59 1-[(2R,4R)-2-(6- fluoro-1H- benzimidazol-2-yl)-1-methylpiperidin- 4-yl]-3-[6- (trifluoromethyl) pyridin-3-yl]ureahydrochloride

104.06 HPLC Rt = 1.9 MS: [M + H] = 437.2 3  60 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-(3-methylbutyl) piperidin-4-yl]- 3-(4-cyanophenyl)urea

104.03 ¹H NMR (CD₃OD, 400 MHz) δ 0.66 (d, 3H), 0.74 (d, 3H), 1.35 (m,2H), 1.42 (m, 1H), 1.82 (m, 1H), 2.00 (m, 2H), 2.18 (m, 2H), 2.40 (m,2H), 3.08 (m, 1H), 3.81 (m, 1H), 4.10 (m, 1H), 7.20 (dd, 2H), 7.50-7.60(m, 6H); HPLC Rf: 2.6 minutes (method, polar/Elmo); ESI- MS: 431 (M +H), 429 (M − H) HPLC Rt = 2.6 MS: [M + H] = 431 4  61 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-benzylpiperidin- 4-yl]-3-(4- cyanophenyl)urea

99.53 ¹H NMR (CD₃OD, 400 MHz) δ 1.79 (m, 1H), 1.97 (m, 1H), 2.08 (m,1H), 2.21 (m, 1H), 2.39 (m, 1H), 2.90 (m, 1H), 3.22 (d, 1H), 3.61 (d,1H), 3.90 (m, 1H), 4.09 (m, 1H), 4.59 (s, 1H), 7.18-7.29 (m, 5H), 7.32(dd, 3H), 7.50-7.60 (m, 5H); HPLC Rf: 2.6 minutes (method, polar/Elmo);ESI- MS: 451 (M + H), 449 (M − H) HPLC Rt = 2.6 MS: [M + H] = 451 4  621-[(2R,4R)-2-(5- methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]-3-[6- (trifluoromethyl) pyridin-3-yl]urea hydrochloride

103.70 HPLC Rt = 1.8 MS: [M + H] = 449.2 3  63 N-[(2R,4R)-2-(6-cyano-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

103.60 HPLC Rt = 1.5 MS: [M + H] = 418.4 1  64 1-[(2R,4R)-2-(5-chloro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(4-cyanophenyl)urea hydrochloride

102.82 HPLC Rt = 1.9 MS: [M + H] = 409.2 4  65 1-[(2R,4R)-1-methyl-2-(5- methyl-1H- benzimidazol-2- yl)piperidin-4-yl]- 3-[6-(trifluoromethyl) pyridin-3-yl]urea hydrochloride

102.77 (CD₃COCD₃) δ 1.82 (m, 2H), 1.9- 2.1 (m, 3H), 2.12 (s, 3H), 2.38(s, 3H), 2.42 (m, 1H), 2.92 (m, 1H), 3.70 (m, 1H), 4.2 (m, 1H), 6.5 (d,1H), 7.0 (d, 1H), 7.32 (s, 1H), 7.4 (d, 1H), 7.68 (d, 1H), 8.24 (d, 1H),8.6 (s, 1H), 8.65 (s, 1H) HPLC Rt = 1.8 MS: [M + H] = 433.2 3  661-[(2R,4R)-2-(1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-y1]-3-[6-(trifluoromethyl) pyridin-3-yl]urea hydrochloride

102.60 HPLC Rt = 1.7 MS: [M + H] = 419.2 3  67 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(2,3- dihydro-1,4-benzodioxin-6- yl)urea hydrochloride

102.53 HPLC Rt = 1.5 MS: [M + H] = 408.2 4  68 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-4- (trifluoroacetyl)benzamide

102.13 HPLC Rt = 1.6 MS: [M + H] = 429.3 1  69 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(5- methylpyridin-3-yl)urea hydrochloride

101.73 HPLC Rt = 1.7 MS: [M + H] = 365.3 3  70 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-cyclobutyl- piperidin- 4-yl]-3-(4-cyanophenyl)urea

101.35 ¹H NMR (CD₃OD, 400 MHz) δ 1.38 (m, 2H), 1.49 (m, 2H), 1.60 (m,1H), 1.79 (m, 1H), 1.90 (m, 3H), 2.23 (m, 1H), 2.49 (m, 1H), 3.02 (m,2H), 3.90 (m, 1H), 4.10 (m, 1H), 7.20 (dd, 2H), 7.50-7.60 (m, 6H); HPLCRf: 2.7 minutes (method, polar/Elmo); ESI- MS: 415 (M + H), 413 (M − H)HPLC Rt = 2.7 MS: [M + H] = 415 4  71 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(5,6- dimethylpyridin-3-yl)urea hydrochloride

101.22 HPLC Rt = 1.5 MS: [M + H] = 379.3 3  72 4-azido-N-[(2R,4R)-2-(1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]benzamide

101.16 HPLC Rt = 1.4 MS: [M + H] = 376.2 1  73 1-[(2R,4R)-2-(6-chloro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[6-(trifluoromethyl) pyridin-3-yl]urea hydrochloride

101.10 HPLC Rt = 2.0 MS: [M + H] = 453.1 3  74 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-pyridin-4-yl-1H-pyrazole-5- carboxamide hydrochloride

100.93 HPLC Rt = 0.8 MS: [M + H] = 400.3 1  75 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-phenylurea hydrochloride

100.46 HPLC Rt = 1.6 MS: [M + H] = 350.3 4  76 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-benzylurea hydrochloride

100.18 HPLC Rt = 2.0 MS: [M + H] = 364.3 4  77 1-[(2R,4R)-2-(5,6-dimethyl-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[6-(trifluoromethyl) pyridin-3-yl]urea hydrochloride

 99.95 HPLC Rt = 1.9 MS: [M + H] = 447.2 3  78 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(5-chloro-2-thienyl)acetamide hydrochloride

 99.29 HPLC Rt = 1.63 MS: [M + H] = 389.2 1  79 N-{(2R,4R)-1-methyl-2-[6- (trifluoromethyl)- 1H-benzimidazol- 2-yl]piperidin-4-yl}-2,3-dihydro-1,4- benzodioxine-6- carboxamide hydrochloride

 99.17 (CD₃OD) δ 1.97 (m, 2H), 2.18 (m, 2H), 2.24 (s, 3H), 2.5 (m, 1H),2.96 (m, 1H), 3.78 (m, 1H), 4.24 (m, 4H), 4.38 (m, 1H), 6.24 (d, 1H),6.85 (d, 1H), 7.24 (m, 2H), 7.3 (s, 1H), 7.45 (s, 1H), 7.4 (b, 1H) HPLCRt = 2.0 MS: [M + H] = 461.1 1  80 1-[(2R,4R)-2-(1H- benzimidazol-2-yl)-1-methylpiperidin- 4-yl]-3-pyridin-3- ylurea hydrochloride

 98.03 HPLC Rt = 1.3 MS: [M + H] = 351.3 4  81 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6- methylpyridin-3-yl)urea hydrochloride

 97.75 HPLC Rt = 1.5 MS: [M + H] = 365.3 3  82 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-cyclobutyl- piperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

 96.77 HPLC Rt =1.5 MS: [M + H] = 433.1 1  83 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6- methoxypyridin-3-yl)urea hydrochloride

 96.06 HPLC Rt = 2.0 MS: [M + H] = 381.2 3  84 1-[(3R,5S)-5-(1H-benzimidazol-2-yl)- 1-isopropyl- pyrrolidin- 3-yl]-3-[4-chloro-3-(trifluoromethyl) phenyl]urea

 95.36 HPLC Rt = 2.3 MS: [M + H] = 466 4  85 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3- cyclopentylureahydrochloride

 93.08 HPLC Rt = 0.7 MS: [M + H] = 342.2 4  86 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

 93.07 HPLC Rt = 1.4 MS: [M + H] = 393 1  87 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-oxo-1,2,3,4-tetrahydroquinoline- 6-carboxamide hydrochloride

 92.32 HPLC Rt = 1.1 MS: [M + H] = 404.3 1  88 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(3- cyanophenyl)ureahydrochloride

 92.14 HPLC Rt = 1.4 MS: [M + H] = 375.2 4  89 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-(cyclopropyl- methyl)piperidin- 4-yl]-2,3-dihydro-1,4- benzodioxine-6- carboxamide hydrochloride

 88.20 HPLC Rt = 1.4 MS: [M + H] = 433 1  90 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(5-phenyl-2- thienyl)ureahydrochloride

 87.90 HPLC Rt = 2.7 MS: [M + H] = 432.1 4  91 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-methyl-6-(trifluoromethyl) nicotinamide hydrochloride

 87.90 HPLC Rt = 1.4 MS: [M + H] = 418.1 1  92 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-4-(1,3-oxazol-5-yl)benzamide hydrochloride

 86.40 HPLC Rt = 1.3 MS: [M + H] = 402.3 1  93 1-[(3S,5S)-5-(1H-benzimidazol-2-yl)- 1-isopropyl- pyrrolidin-3-yl]- 3-[4-chloro-3-(trifluoromethyl) phenyl]urea

 85.20 HPLC Rt = 2.3 MS: [M + H] = 466 4  94 N-[(2R,4S)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

 79.70 HPLC Rt = 1.6 MS: [M + H] = 393.1 1  95 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]morpholine-4- carboxamidehydrochloride

 78.70 HPLC Rt = 1.6 MS: [M + H] = 344.3 3  96 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(5- methoxypyridin-3-yl)urea hydrochloride

 76.30 HPLC Rt = 2.4 MS: [M + H] = 381.2 3  97 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3- dihydro[1,4]dioxino[2,3-b]pyridine-7- carboxamide hydrochloride

 75.40 HPLC Rt = 1.1 MS: [M + H] = 394.3 1  98 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-(2-phenyl- ethyl)piperidin- 4-yl)-3-(4-cyanophenyl)urea

 74.50 ¹H NMR (CD₃OD, 400 MHz) δ 1.83- 1.87 (m, 1H), 1.99-2.13 (m, 3H),2.42-2.46 (m, 1H), 2.58- 2.70 (m, 3H), 2.78-2.82 (m, 1H), 3.14-3.18 (m,2H), 3.91- 3.94 (m, 1H), 4.08-4.10 (m, 1H), 6.95 (d, 2H), 7.15-7.10 (m,3H), 7.21 (dd. 2H), 7.49-7.59 (m, 6H); HPLC Rt = 2.8 MS: [M + H] = 465 4 99 N-[(2R,4R)-2-(1H- benzimidazol-2- yl)piperidin-4-yl]-2,3-dihydro-1,4- benzodioxine-6- carboxamide trifluoroacetate

 72.00 HPLC Rt = 1.3 MS: [M + H] = 379 1 100 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-oxo-3,4- dihydro-2H-1,4-benzoxazine-6- carboxamide hydrochloride

 63.70 HPLC Rt = 1.3 MS: [M + H] = 406 1 101 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-[5- (trifluoromethyl)pyridin-2-yl]urea hydrochloride

 62.50 HPLC Rt = 1.8 MS: [M + H] = 419.2 3 102 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-4-fluoro-3-methoxybenzamide trifluoroacetate

102.0  HPLC Rt = 1.09 MS: [M + H] = 383.23 1 103 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-6- methylquinoline-4-carboxamide trifluoroacetate

100.0  HPLC Rt = 0.92 MS: [M + H] = 400.27 1 104 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(1- benzofuran-2-yl)acetamide trifluoroacetate

99.5 HPLC Rt = 1.16 MS: [M + H] = 389.24 1 105 (2S)-N-[(2R,4R)-2-(1H-benzimidazol- 2-yl)-1- methylpiperidin-4- yl]-2,3-dihydro-1,4-benzodioxine-2- carboxamide trifluoroacetate

97.8 HPLC Rt = 1.13 MS: [M + H] = 393.23 1 106 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(2H-1,2,3-benzotriazol-2- yl)acetamide trifluoroacetate

94.5 HPLC Rt = 1.05 MS: [M + H] = 390.25 1 107 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2- (methylthio) benzamidetrifluoroacetate

88.3 HPLC Rt = 1.06 MS: [M + H] = 381.21 1 108 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(2H- indazol-2-yl)acetamide trifluoroacetate

86.4 HPLC Rt = 1.08 MS: [M + H] = 389.26 1 109 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(1H- indazol-1-yl)acetamide trifluoroacetate

85.2 HPLC Rt = 1.07 MS: [M + H] = 389.25 1 110 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2- phenylacetamidetrifluoroacetate

83.2 HPLC Rt = 1.07 MS: [M + H] = 349.23 1 111 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-4- methoxybenzamidetrifluoroacetate

83.2 HPLC Rt = 1.02 MS: [M + H] = 365.24 1 112 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3- methoxybenzamidetrifluoroacetate

81.7 HPLC Rt = 1.04 MS: [M + H] = 365.23 1 113 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-1-methyl-1H- indole-2-carboxamide trifluoroacetate

76.1 HPLC Rt = 1.27 MS: [M + H] = 388.26 1 114 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(1,3- benzoxazol-2-yl)acetamide trifluoroacetate

75.5 HPLC Rt = 0.94 MS: [M + H] = 408.27 1 115 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]pyrazolo[1,5- a]pyridine-3-carboxamide trifluoroacetate

69.6 HPLC Rt = 0.91 MS: [M + H] = 375.25 1 116 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(2,3- dihydro-1-benzofuran-5- yl)acetamide trifluoroacetate

68.2 HPLC Rt = 1.06 MS: [M + H] = 391.27 1 117 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-fluoro-4-methoxybenzamide trifluoroacetate

65.4 HPLC Rt = 1.12 MS: [M + H] = 383.22 1 118 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-7- methylpyrazolo[1,5-a]pyridine-2- carboxamide trifluoroacetate

65.1 HPLC Rt = 1.1 MS: [M + H] = 389.25 1 119 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,1,3- benzoxadiazole-5-carboxamide trifluoroacetate

64.5 HPLC Rt = 1.11 MS: [M + H] = 377.21 1 120 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(2- fluorophenyl)acetamide trifluoroacetate

63.7 HPLC Rt = 1.07 MS: [M + H] = 367.22 1 121 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-4- cyanobenzamidetrifluoroacetate

62.3 HPLC Rt = 0.99 MS: [M + H] = 360.23 1 122 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2(2-difluoro-2-phenylacetamide trifluoroacetate

57.5 HPLC Rt = 1.22 MS: [M + H] = 385.24 1 123 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2-(3- fluorophenyl)acetamide trifluoroacetate

52.2 HPLC Rt = 1.08 MS: [M + H] = 367.22 1 124 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-1-tert-butyl-3- methyl-1H-pyrazole-5- carboxamide trifluoroacetate

50.6 HPLC Rt = 1.08 MS: [M + H] = 395.3 1 125 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-cyclopropyl piperidin-4- yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide hydrochloride

102.06 (acetone-D6) 0.3-0.5 (m, 4H), 1.8 (m, 2H), 2.16 (m, 2H), 2.48 (m,1H), 2.88 (m, 1H), 3.14 (m, 1H), 4.28 (m, 4H), 4.4 (m, 1H), 4.5 (m, 1H),6.8 (d, 1H), 7.1 (m, 2H), 7.4 (m, 2H), 7.42 (m, 1H), 7.53 (m, 1H) HPLCRt = 1.7 MS: [M + H] = 419.2 2 126 1-[(2R,4R)-2-(6- chloro-1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6- methylpyridin-3-yl)urea hydrochloride

110.0  HPLC Rt = 1.8 MS: [M + H] = 399.2 3 127 1-[(2R,4R)-2-(5-cyano-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6-methylpyridin-3- yl)urea hydrochloride

103.0  HPLC Rt = 1.5 MS: [M + H] = 390.2 3 128 1-(6-methylpyridin-3-yl)-3-{(2R,4R)-1- methyl-2-[5- (trifluoromethyl)- 1H-benzimidazol-2-yl]piperidin-4- yl}urea hydrochloride

102.34 (acetone-D6) 1.8 (m, 1H), 2.04 (m, 1H), 2.18 (m, 2H), 2.22 (s,3H), 2.40 (s, 3H), 2.62 (m, 1H), 3.0 (m, 1H), 3.94 (m, 1H), 4.18 (m,1H), 6.4 (d, !H), 7.05 (d, 1H), 7.45 (d, 1H), 7.7 (d, 1H), 7.9 (m, 2H),8.08 (s, 1H), 8.42 (s, 1H) HPLC Rt = 1.1 MS: [M + H] = 433.2 3 1291-[(2R,4R)-2-(5- methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]-3-(6- methylpyridin-3- yl)urea hydrochloride

103.83 HPLC Rt = 0.08 MS: [M + H] = 395.2 3 130 1-[(2R,4R)-1-methyl-2-(5- methyl-1H- benzimidazol-2- yl)piperidin-4-yl]-3-(6-methylpyridin-3- yl)urea hydrochloride

106.1  HPLC Rt = 0.9 MS: [M + H] = 379.2 3 131 1-[(2R(4R)-2-(5,6-dimethyl-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6-methylpyridin-3- yl)urea hydrochloride

104.86 HPLC Rt = 1.00 MS: [M + H] = 393.3 132 1-[(2R,4R)-2-(6-fluoro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6-methylpyridin-3- yl)urea hydrochloride

107.75 HPLC Rt = 0.4 MS: [M + H] = 383.2 3 133 1-[(2R,4R)-2-(6-chloro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6-methoxypyridin-3- yl)urea hydrochloride

107.55 HPLC Rt = 1.6 MS: [M + H] = 415 3 134 1-[(2R,4R)-2-(5- cyano-1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6- methoxypyridin-3-yl)urea hydrochloride

104.78 HPLC Rt = 1.2 MS: [M + H] = 406.2 3 135 1-(6- methoxypyridin-3-yl)-3-{(2R,4R)-1- methyl-2-[5- (trifluoromethyl)- 1H-benzimidazol-2-yl]piperidin-4- yl}urea hydrochloride

103.51 HPLC Rt = 1.7 MS: [M + H] = 449.2 3 136 1-[(2R,4R)-2-(5-methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-y)]-3-(6-methoxypyridin-3- yl)urea hydrochloride

105.82 HPLC Rt = 1.4 MS: [M + H] = 411.1 3 137 1-{6- methoxypyridin-3-yl)-3-[(2R.4R)-1- methyl-2-(5- methyl-1H- benzimidazol-2-yl)piperidin-4- yl]urea hydrochloride

102.48 (acetone-D6) 1.8 (m, 1H), 1.9 (m, 1H), 2.08 (m, 2H), 2.38 (s,3H), 2.42 (m, 1H), 2.84 (m, 1H), 3.68 (m, 1H), 3.8 (s, 3H), 4.18 (m,1H), 6.22 (d, !H), 6.6 (d, 1H), 7.0 (d, 1H), 7.37 (s, 1H), 7.94 (m, 1H),7.8 (dd, 1H), 8.0 (s, 1H), 8.1 (s, 1H) HPLC Rt = 1.4 MS: [M + H] = 395.13 138 1-[(2R,4R)-2-(5,6- dimethyl-1H- benzimidazol-2-yl)-1-methylpiperidin- 4-yl]-3-(6- methoxypyridin-3- yl)urea hydrochloride

107.67 HPLC Rt = 1.5 MS: [M + H] = 409.2 3 139 1-[(2R,4R)-2-(6-fluoro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-3-(6-methoxypyridin-3- yl)urea hydrochloride

106.32 (acetone-D6) 1.8 (m, 1H), 1.85- 2.0 (m, 2H), 2.05 (m, 1H), 2.1(s, 3H), 2.42 (m, 1H), 2.82 (m, 1H), 3.64 (m, 1H), 3.8 (s, 3H), 4.18 (m,1H), 6.17 (d, 1H), 6.6 (d, 1H), 7.0 (m, 1H), 7.2 (d, 1H), 7.5 (b, 1H),7.82 (m, 2H), 8.2 (s, 1H) HPLC Rt = 1.2 MS: [M + H] = 399.2 3 140N-[(2R,4R)-2-(1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]-2,3-dihydro- 1,4-benzodioxine- 6-carbothioamide hydrochloride

106.94 HPLC Rt = 1.7 MS: [M + H] = 409.1 1 141 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-5-fluoro-2,3- dihydro-1,4-benzodioxine-6- carboxamide trifluoroacetate

85.3 HPLC Rt = 1.3 MS: [M + H] = 411.3 1 142 N-[(2R,4R)-2-(5- chloro-1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-5-fluoro-2,3- dihydro-1,4-benzodioxine-6- carboxamide triflouroacetate

100.91 HPLC Rt = 1.7 MS: [M + H] = 445.1 1 143 5-fluoro-N-[(2R,4R)-2-(5- methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]-2,3-dihydro- 1,4-benzodioxine- 6-carboxamide triflouroacetate

83.5 HPLC Rt = 1.3 MS: [M + H] = 441.1 1 144 N-[(2R,4R)-2-(1H-benzimidazol- 2-yl)-1- methylpiperidin-4- yl]-5-chloro-2,3-dihydro-1,4- benzodioxine-6- carboxamide triflouroacetate

107.73 HPLC Rt = 1.2 MS: [M + H] = 427.1 1 145 5-chloro-N-[(2R,4R)-2-(5- chloro-1H- benzimidazol-2-yl)- 1-methylpiperidin-4-yl]-2,3-dihydro- 1,4-benzodioxine- 6-carboxamide triflouroacetate

106.34 HPLC Rt = 1.5 MS: [M + H] = 461 1 146 5-chloro-N- [(2R,4R)-2-(5-methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide triflouroacetate

106.53 HPLC Rt = 1.1 MS: [M + H] = 457.1 1 147 N-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-7-chloro-2,3- dihydro-1,4-benzodioxine-6- carboxamide triflouroacetate

69.5 HPLC Rt = 1.3 MS: [M + H] = 427.1 148 7-chloro-N- [(2R,4R)-2-(5-chloro-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide triflouroacetate

 94.97 HPLC Rt = 1.6 MS: [M + H] = 461 1 149 7-chloro-N- [(2R,4R)-2-(5-methoxy-1H- benzimidazol-2-yl)- 1-methylpiperidin- 4-yl]-2,3-dihydro-1,4-benzodioxine- 6-carboxamide triflouroacetate

35.3 HPLC Rt = 1.4 MS: [M + H] = 457.1 1 150 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)- 1-cyclobutyl- piperidin- 4-yl]-3-(6-methylpyridin-3- yl)urea triflouroacetate

106.11 HPLC Rt = 0.9 MS: [M + H] = 405.2 3 151 1-[(2R,4R)-1-cyclobutyl-2-(5- methy-1H- benzimidazol-2- yl)piperidin-4-yl]-3-(6-methylpyridin-3- yl)urea triflouroacetate

106.65 HPLC Rt = 1.1 MS: [M + H] = 419.2 3 152 1-[(2R,4R)-1-cycobutyl-2-(5,6- dimethy-1H- benzimidazol-2- yl)piperidin-4-yl]-3-(6-methylpyridin-3- yl)urea triflouroacetate

106.17 HPLC Rt = 2.0 MS: [M + H] = 433.2 3 153 1-[(2R,4R)-1-cyclobutyl-2-(5- methoxy-1H- benzimidazol-2- y1)piperidin-4-yl]-3-(6-methylpyridin-3- yl)urea triflouroacetate

106.60 HPLC Rt = 1.1 MS: [M + H] = 435.2 3

1. A pharmaceutical composition, comprising a compound which is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 2. A method of treating abnormal cellgrowth in a mammal, comprising administering to said mammal an amount ofa compound which is

or a pharmaceutically acceptable salt thereof, that is effective intreating abnormal cell growth.
 3. The method of claim 2, wherein saidabnormal cell growth is cancer.
 4. The method of claim 3, wherein saidcancer is selected from the group consisting of basal cell cancer,medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head, cancerof the neck, cutaneous melanoma, intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, and pituitary adenoma.